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{{short description|Blood serum containing antibodies; used to spread passive immunity}}
{{about|the applications of antiserum|an explanation of its production|polyclonal antibodies}}
{{cleanup|reason=Dives too deep into monoclonal, which mostly isn’t produced by live humans (or domestic animals) donating their serum, even in "modern use"! Antiserum needs to be serum or derived from it.|date=January 2023}}
 
In [[immunology]], '''Antiserumantiserum''' is human or nonhumana [[blood serum]] containing monoclonal[[antibodies]] or(either [[polyclonalMonoclonal responseantibody|polyclonalmonoclonal]] or [[polyclonal antibodies|polyclonal]]) that is used to spread [[passive immunity]] to many diseases via [[blood donation]] ([[plasmaphoresisplasmapheresis]]). For example, '''convalescent serum''', passive antibody [[Blood transfusion|transfusion]] from a previous human survivor, used to be the only known effective treatment for [[ebola]] infection with a high success rate of 7 out of 8 patients surviving.<ref>{{cite journal|last1=Mupapa|first1=K|last2=Massamba|first2=M|last3=Kibadi|first3=K|last4=Kuvula|first4=K|last5=Bwaka|first5=A|last6=Kipasa|first6=M|last7=Colebunders|first7=R|last8=Muyembe-Tamfum|first8=JJ|title=Treatment of Ebola Hemorrhagic Fever with Blood Transfusions from Convalescent Patients |journal=The Journal of Infectious Diseases|date=1999|issue=179|pages=S18–S23|doi=10.1086/514298|pmid=9988160|volume=179 Suppl 1|doi-access=free}}</ref>
 
Antisera are widely used in diagnostic [[virology]] laboratories. The most common use of antiserum in humans is as [[antitoxin]] or [[antivenom]] to treat [[envenomation]].{{cn|date=November 2023}}
 
'''Serum therapy''', also known as '''serotherapy''', describes the treatment of infectious disease using the serum of animals that have been immunized against the specific organisms or their product, to which the disease is supposedly referable.{{cn|date=November 2023}}
 
== History ==
In 1890, [[Emil Behring]] and [[Kitasato Shibasaburō]] published their first paper on serum therapy.
The first therapies for the treatment of [[diphtheria]] and [[tetanus]] came into use in the mid-1890s and had a major impact on the development of the history of medicine.
 
[[Emil von Behring|Emil Behring]] (1854–1917) had pioneered the technique, using guinea pigs to produce serum.<ref>{{cite web |last1=Grundmann |first1=Kornelia |title=Emil von Behring: The Founder of Serum Therapy |url=https://www.nobelprize.org/prizes/medicine/1901/behring/article/ |website=NobelPrize.org |publisher=Nobel Media AB 2021 |access-date=8 June 2021}}</ref> Based on his observation that people who survived infection with the [[Corynebacterium diphtheriae|diphtheria bacterium]] never became infected again, he discovered that the body continually produces an [[antitoxin]], which prevents survivors of infections from being infected again with the same agent.
 
It was necessary for Behring to immunize larger animals in order to produce enough serum to protect humans, because the amount of antiserum produced by guinea pigs was too little to be practical. Horses proved to be the best serum producer, as the serum of other large animals is not concentrated enough, and horses were not believed to carry any [[zoonosis|diseases that could be transferred to humans]].
 
Due to the [[World War I|First World War]], a large number of horses were needed for military purposes. It was difficult for Behring to find enough German horses for his serum facility. He chose to obtain horses from [[Eastern Europe]]an countries, mostly Hungary and Poland. Because of Behring's limited financial resources, most horses he selected had been intended for slaughter; however, the usefulness of the animal to others had no influence on the production of serum. Serum horses were calm, well-mannered, and in good health. Age, breed, height, and color were irrelevant.<ref>{{Cite web|url=httphttps://www.animalresearch.info/en/medical-advances/nobel-prizes/serum-therapy-especially-its-application-against-diphtheria/|title=Serum therapy, especially in its application against diphtheria.}}</ref>
 
Horses were transported from Poland or Hungary to the Behring facilities in Marburg, in the west-central part of Germany. Most of the horses were transported by rail and treated like any other freight load. During the interminable border crossing, horses were left at the mercy of the weather.<ref>{{Cite book|title=Die Stute Namenlos|last=Kautz|first=Gisela|publisher=Thienemann-Esslinger|year=2004|isbn=978-3522176446|location=Stuttgart}}</ref> Once the horses arrived in [[Marburg]], they had three to four weeks to recover in a quarantine facility, where data on them was recorded. They had to be in perfect medical condition for the immunization, and the quarantine facility ensured that they were free of microbes which could infect the other horses. In the Behring facilities, the horses were viewed as life savers; therefore, they were well treated. A few of the individual horses used for serum production were [[Personal name#Names of pets|named]], and celebrated for their service to medicine, both human and [[veterinary medicine|non-human]].
[[File:Convalescent plasma collected during COVID-19 pandemic.jpg|thumb|right|300px|[[Convalescent plasma]] collected at a blood donor center during the [[COVID-19 pandemic]].]]
At the end of the 19th century, every second child in Germany was infected with diphtheria, the most frequent cause of death in children up to 15 years. In 1891 [[Emil von Behring|Emil Behring]] saved the life of a young girl with diphtheria by injecting antiserum for the first time in history. Serum horses proved to be saviors of diphtheria-infected people. Subsequently, treatment of [[tetanus]], [[rabies]], and [[snake venom]] developed, and proactive protective vaccination against diphtheria and other microbial diseases began.
 
In 1901, Behring won the first [[Nobel Prize in Physiology or Medicine|Nobel Prize in Medicine]] for his work in the study of [[diphtheria]].
 
Serum therapy became increasingly prevalent for infectious diseases, and was even used to treat patients during the [[Influenza Pandemic|influenza pandemic in 1918]]. Its uses were then quickly expanded to also treat diseases such as [[polio]], [[measles]], [[pneumococcus]], [[Haemophilus Influenzae|Haemophilus influenza B]], and [[meningococcus]]. In the 1920s, [[Michael Heidelberger]] and [[Oswald Avery]] proved that [[Antibody|antibodies]] were proteins that targeted the capsule of the [[virus]] or [[bacteria]].
 
The discovery of [[antibiotics]] in the 1940s diminished interest in treating bacterial infections with antiserum, but its use for viral infections continued with the development of [[Cohn process|ethanol fractionation]] of blood plasma (which allowed for purified antibodies), discovered by [[Edwin Joseph Cohn|Dr. Edwin Cohn]]. Antisera were developed to prevent and/or treat [[diphtheria]], [[tetanus]], [[Hepatitis B]], [[rabies]], [[varicella zoster virus]], [[cytomegalovirus]], and [[botulinum]]. However, these were not widely used.
 
In 1984, [[César Milstein|Milstein]] and [[Georges J. F. Köhler|Köhler]] won a Nobel Prize for their paper that described their method for making murine [[monoclonal antibody|monoclonal antibodies]] by immortalizing [[B Cell| B cells]] as [[Hybridoma Technology|hybridomas]]. Another breakthrough occurred in 2003. A new technology allowed for heavy and light chain immunoglobulin genes to be amplified from human B cells and cloned into [[expression vector|expression vectors]]s. In 2008, this method was refined with a greater ability to sort cells and clone, which led to the discovery of more human monoclonal antibodies.
 
In 1996, the FDA approved the use of RSV-IGIV (Respigam®), a polyclonal antibody drug to inhibit [[respiratory syncytial virus]] (RSV) for high-risk newborns. This was considered a breakthrough, as the clinical trial was proven to reduce infant hospitalizations by 41% and length of hospital stays by 53%. After two years the product demand began to exceed the supply of plasma and [[Palivizumab|Synagis®]], the first humanized monoclonal antibody was approved in its place. Monoclonal antibodies became advantageous due to their decreased variability in quality, a decreased risk of bloodborne diseases, and increased potency. This enabled a large expansion of the usages of antiserum and opened the door for the treatment of autoimmune diseases.
 
The past 30 years have seen the transformation of how chronic and autoimmune diseases (e. g. [[cancer]], [[ulcerative colitis]]) are treated, with 30 drugs—28 of which for chronic conditions—with monoclonal antibodies being approved. Monoclonal antibodies are currently being researched to treat viral diseases without vaccines, such as [[HIV]], [[SARS]], and [[MERS]].<ref>{{cite journal |last1=Graham |first1=Barney S. |last2=Ambrosino |first2=Donna M. |title=History of Passive Antibody Administration for Prevention and Treatment of Infectious Diseases |journal=Current Opinion in HIV and AIDS |date=May 2015 |volume=10 |issue=3 |pages=129–134 |doi=10.1097/COH.0000000000000154 |pmid=25760933 |pmc=4437582 |issn=1746-630X}}</ref>
 
==Modern use==
{{For |a more complete list of monoclonal antibodies visit [[|list of therapeutic monoclonal antibodies]].}}
 
For a more complete list of monoclonal antibodies visit [[list of therapeutic monoclonal antibodies]].
 
Monoclonal antibodies are used to treat both [[acute (medicine)|acute]] and [[chronic condition|chronic]] conditions. Acute conditions may include, but are not limited to Ebola virus, envenomation (e. g. snake bites), and [[anthrax]] infection. Chronic conditions may include, but are not limited to [[rheumatoid arthritis]], [[ulcerative colitis]], and [[lupus]].<ref name="scicomvisuals" />
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There are four main types of monoclonal antibodies. They are murine, chimeric, humanized, and human.
 
Murine monoclonal antibodies are identified with the suffix "-omab". They originate from a [[murine]] animalanimals and can trigger allergic reactions in humans.<ref name="miller">{{cite web |last1=Miller |first1=Justine |title=What is a Monoclonal Antibody? |url=https://nicb.ie/biotechnology/what-is-a-monoclonal-antibody/ |website=National Institute for Cellular Biotechnology |publisher=National Institute for Cellular Biotechnology |date=2016-08-08}}</ref> An example of a murine monoclonal antibody is [[Blinatumomabblinatumomab]], which is used to treat [[acute lymphoblastic leukemia]].<ref name="scicomvisuals">{{cite web |title=Antibody therapeutics approved or in regulatory review in the EU or US |url=https://www.antibodysociety.org/resources/approved-antibodies/ |website=The Antibody Society |publisher=Scicomvisuals}}</ref>
 
HumanChimeric monoclonal antibodies are identified with the suffix "-umabximab". They originate partially from a murine animal and partially from a human.<ref name="miller" /> An example of a humanchimeric monoclonal antibody is [[Ustekinumabinfliximab]], which treatsis used to treat [[psoriasisCrohn disease]].<ref name="scicomvisuals" />
 
ChimericHumanized monoclonal antibodies are identified with the suffix "-ximabzumab". They mostly originate partially from a murinehuman animalbut anddiffer partiallyin fromthe acomponent humanthat attaches to its target.<ref name="miller" /> An example of a chimerichumanized monoclonal antibody is [[Infliximabcrizanlizumab]], which is used to treattreats [[Crohnsickle cell disease]].<ref name="scicomvisuals" />
 
HumanizedHuman monoclonal antibodies are identified with the suffix "-zumabumab". They mostly originate from a human but differ in the component that attaches to its target.<ref name="miller" /> An example of a humanizedhuman monoclonal antibody is [[Crizanlizumabustekinumab]], which treats [[sickle cell diseasepsoriasis]].<ref name="scicomvisuals" />
 
During the early stages of the [[COVID-19 pandemic]], reliable treatment options had not yet been found or approved. In reaction, convalescent blood plasma was considered as a possibility and is used as a treatment option at least for severe cases.<ref>{{Cite web|url=https://ec.europa.eu/health/blood_tissues_organs/covid-19_en|title=COVID-19 Convalescent Plasma Transfusion|date=8 April 2020}}</ref><ref>{{Cite web|url=https://www.pei.de/EN/newsroom/press-releases/year/2020/07-pei-approves-first-covid-19-therapy-study-with-convalescent-plasma.html|title = Paul-Ehrlich-Institut - Press Releases - Paul-Ehrlich-Institut Approves First COVID-19 Therapy Study with Convalescent Plasma}}</ref><ref>{{Cite web |title=Convalescent Plasma COVID-19 Emergency Use Authorization |url=https://www.uscovidplasma.org/ |access-date=2023-02-20 |website=Convalescent Plasma COVID-19 Emergency Use Authorization |language=en}}</ref> In May 2021, India was one of the first major country to remove plasma from its national COVID-19 guidelines. This was after public criticism of the lack of plasma's effectiveness, criticism of health systems, and persuasion by leading Indian scientists including Shahid Jameel, [[Soumyadeep Bhaumik]], Gagandeep Kang, [[Soumitra Pathare]], and others.<ref>{{Cite web|last=Livemint|date=2021-05-11|title=Call off plasma therapy for patients of covid-19|url=https://www.livemint.com/opinion/online-views/call-off-plasma-therapy-for-patients-of-covid19-11620752200055.html|access-date=2022-02-04|website=mint|language=en}}</ref><ref>{{Cite web|date=2021-05-10|title=Plasma therapy for Covid 'irrational, non-scientific', change guidelines, experts ask govt|url=https://theprint.in/health/plasma-therapy-for-covid-irrational-non-scientific-change-guidelines-experts-ask-govt/656058/|access-date=2022-02-04|website=ThePrint|language=en-US}}</ref><ref>{{Cite web|last=Staff|first=The Wire|title=COVID: Public Health Experts Pen Concerns About Plasma to PSA VijayRaghavan – The Wire Science|url=https://science.thewire.in/health/covid-public-health-experts-pen-concerns-about-plasma-to-psa-vijayraghavan/|access-date=2022-02-04|language=en-GB}}</ref><ref>{{Cite web|last=Buckshee|first=Devina|date=2021-05-18|title=Plasma Dropped from COVID Guidelines: What About HCQ, Ivermectin?|url=https://fit.thequint.com/coronavirus/plasma-dropped-from-covid-guidelines-what-about-hcq-ivermectin|access-date=2022-02-04|website=TheQuint|language=en}}</ref> The World Health Organization recommended against use of plasma in COVID-19 in December 2021.<ref>{{Cite web|title=WHO recommends against the use of convalescent plasma to treat COVID-19|url=https://www.who.int/news/item/07-12-2021-who-recommends-against-the-use-of-convalescent-plasma-to-treat-covid-19|access-date=2022-02-04|website=www.who.int|language=en}}</ref>
Human monoclonal antibodies are identified with the suffix "-umab". They originate from a human.<ref name="miller" /> An example of a human monoclonal antibody is [[Ustekinumab]], which treats [[psoriasis]].<ref name="scicomvisuals" />
 
DuringMonoclonal the early stages of theantibodies ([[COVID-19 pandemiccasirivimab/imdevimab]], reliable treatment options had not been found. In reaction, convalescent blood plasma was considered as a possibility and is used as a treatment option at least for severe cases.<ref>{{Cite web|url=https://ec.europa.eu/health/blood_tissues_organs/covid-19_en|title=COVID-19 Convalescent Plasma Transfusion|date=8 April 2020}}</ref><ref>{{Cite web|url=https://www.pei.de/EN/newsroom/press-releases/year/2020/07-pei-approves-first-covid-19-therapy-study-with-convalescent-plasma.html|title = Paul-Ehrlich-Institut - Press Releases - Paul-Ehrlich-Institut Approves First COVID-19 Therapy Study with Convalescent Plasma}}</ref><ref>https://www.uscovidplasma.org/</ref> Subsequently, monoclonal antibodies (Casirimivab and Imdemivab) were developed for the treatment of COVID-19.<ref>{{cite web |title=Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19 |url=https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19 |website=FDA |language=en |date=2020-11-23}}</ref>
 
On June 7, 2021, the FDA approved [[Aducanumabaducanumab]], the first [[Alzheimer's disease|Alzheimer's]] drug in 20 years.<ref>{{cite web |title=FDA Grants Accelerated Approval for Alzheimer's Drug |url=https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug |website=FDA |language=en |date=2021-06-07}}</ref> the first anti-[[Alzheimer's disease|Alzheimer's]] drug to be introduced into markets almost 20 years after approval of [[memantine]] in 2003.<ref>{{Cite journal |last=Lo |first=Daphne |last2=Grossberg |first2=George T. |date=October 2011 |title=Use of memantine for the treatment of dementia |url=https://pubmed.ncbi.nlm.nih.gov/21955192/#:~:text=In%202003,%20memantine,moderate-to-severe%20AD. |journal=Expert Review of Neurotherapeutics |volume=11 |issue=10 |pages=1359–1370 |doi=10.1586/ern.11.132 |issn=1744-8360 |pmid=21955192}}</ref>
 
==How it works==
Antibodies in the antiserum bind the infectious agent or [[antigen]].<ref>{{cite journal |last1=de Andrade |first1=Fábio Goulart |last2=Eto |first2=Silas Fernandes |last3=Navarro dos Santos Ferraro |first3=Ana Carolina |last4=Gonzales Marioto |first4=Denise Turini |last5=Vieira |first5=Narciso Júnior |last6=Cheirubim |first6=Ana Paula |last7=de Paula Ramos |first7=Solange |last8=Venâncio |first8=Emerson José |title=The production and characterization of anti-bothropic and anti-crotalic IgY antibodies in laying hens: A long term experiment |journal=Toxicon |date=May 2013 |volume=66 |pages=18–24 |doi=10.1016/j.toxicon.2013.01.018|pmid=23416799 }}</ref> The [[immune system]] then recognizes foreign agents bound to antibodies and triggers a more robust [[immune response]]. The use of antiserum is particularly effective against pathogens which are capable of evading the immune system in their unstimulated state but are not robust enough to evade the stimulated immune system. The existence of antibodies to the agent depends on an initial survivor whose immune system, by chance, discovered a counteragent to the pathogen or a host species which carries the pathogen but does not suffer fromexperience its effects.<ref>{{cite journal |last1=Mortimer |first1=Nathan T. |last2=Goecks |first2=Jeremy |last3=Kacsoh |first3=Balint Z. |last4=Mobley |first4=James A. |last5=Bowersock |first5=Gregory J. |last6=Taylor |first6=James |last7=Schlenke |first7=Todd A. |title=Parasitoid wasp venom SERCA regulates Drosophila calcium levels and inhibits cellular immunity |journal=Proceedings of the National Academy of Sciences |date=2013-06-04 |volume=110 |issue=23 |pages=9427–9432 |doi=10.1073/pnas.1222351110|pmid=23690612 |pmc=3677475 |bibcode=2013PNAS..110.9427M |s2cid=8954855 |doi-access=free }}</ref> Further stocks of antiserum can then be produced from the initial donor or from a donor organism that is inoculated with the pathogen and cured by some stock of pre-existing antiserum. Diluted snake venom is often used as an antiserum to give passive immunity to snake venom itself.<ref>{{cite journal |last1=O'Leary |first1=M.A. |last2=Maduwage |first2=K. |last3=Isbister |first3=G.K. |title=Use of immunoturbidimetry to detect venom–antivenom binding using snake venoms |journal=Journal of Pharmacological and Toxicological Methods |date=May 2013 |volume=67 |issue=3 |pages=177–181 |doi=10.1016/j.vascn.2013.02.004|pmid=23416032 |hdl=1959.13/1045701 |hdl-access=free }}</ref><ref>{{cite journal |last1=Vogel |first1=Carl-Wilhelm |last2=Finnegan |first2=Paul W. |last3=Fritzinger |first3=David C. |title=Humanized cobra venom factor: Structure, activity, and therapeutic efficacy in preclinical disease models |journal=Molecular Immunology |date=October 2014 |volume=61 |issue=2 |pages=191–203 |doi=10.1016/j.molimm.2014.06.035|pmid=25062833 }}</ref>10.1016/j.molimm.2014.06.035
 
Horses that were infected by a pathogen were vaccinated thrice in increasing sizes of the dose. The time between each vaccination varied from each horse and its health condition. Normally the horses needed a few weeks to produce the serum in the blood after the last vaccination. Even though they tried to empower the immune system of the horses during this immunization with painstaking care, most of the horses sufferedexperienced appetite loss, [[fever]], and in worse cases [[Shock (circulatory)|shock]] and [[Shortness of breath|dyspnea]].{{citation needed|date=June 2022}}
 
The highest immunization risk for horses was the production of antiserum for snake venom.