key: cord-0847664-76qdrq98
authors: Pelletier, J. Peter R.; Mukhtar, Faisal
title: Chapter 16 Passive Monoclonal and Polyclonal Antibody Therapies
date: 2020-12-31
journal: Immunologic Concepts in Transfusion Medicine
DOI: 10.1016/b978-0-323-67509-3.00016-0
sha: f30cb43b0f024fc448ed3bcd87ee59acb54617d3
doc_id: 847664
cord_uid: 76qdrq98

Abstract Passive antibody therapies have a long history of use. In the 19th century, antibodies from xenographic sources of polyclonal antibodies were used to treat infections (diphtheria). They were used often as protection from infectious agents and toxins. Complications related to their use involved development of immune complexes and severe allergic reactions. As a result, human source plasma for polyclonal antibodies became the preferential source for antibodies. They are used to treat infection, remove toxins, prevent hemolytic disease of the newborn, modify inflammatory reactions, and control autoimmune diseases. Continued improvements in processing decreased the transfusion/infusion transmission of infections. In the late 20th century (∼1986), monoclonal antibodies were developed. The first monoclonal antibodies were of xenographic source and were wrought with problems of immunogenicity. These forms of antibodies did not gain favor until chimerization took pace in the mid-1990s and in 1998 two monoclonal antibodies were approved one to treat respiratory syncytial virus and the other for breast cancers. Further development of humanized and then fully human monoclonal antibodies has led to an evolution of therapies with these agents. Monoclonal antibodies are being researched or approved to treat a multitude of diseases to include oncologic, inflammatory, autoimmune, cardiovascular, respiratory, neurologic, allergic, benign hematologic, infections, orthopedic, coagulopathy, metabolic and to decrease morbidity of disease (diminution of pain), modify disease progression, and potentially anatomic development. In this chapter, we will review the history of use of these passive antibody therapies, their mechanism of action, pharmacologic-therapeutic classification, particular medical indication, adverse reactions, and potential future use of these medications.

Polyclonal immunoglobulins have been in use since the 19th century to protect against infectious agents, toxins, and disease conditions such as those with an autoimmune etiology. These immunoglobulin preparations are made from pools of selected human donors or animals with high titers of antibodies against viruses and toxins. These antibody treatments provide passive transfer of high titer antibodies that either reduces risk or reduces severity of infection. They are used to prevent hemolytic disease of the newborn and modify inflammatory reactions. Earlier drugs were very nonselective and patients frequently succumbed to infection due to suppression of both antibody-mediated (humoral) and cell-mediated arms of the immune system. Today, the principal approach is to alter lymphocyte function using drugs or antibodies against immune proteins. However, with the advent of human organ and tissue transplantation (e.g., kidney, heart, bone marrow, and/or peripheral blood stem cells) as treatment options, these polyclonal antibody therapies in combination with other treatment regimens are being used to lower the ability of the body's immune system to reject these transplants. However, their use is not without risk, as complications include development of immune complexes and severe allergic reactions. A summary of these polyclonal antibody therapies may be found in Table 16 .2.

Immunosuppressive Agents: Disease Modifying Antithymocyte globulin (rabbit)/thymoglobulin; antithymocyte globulin (equine)/Atgam Description. Rabbit antithymocyte globulin (rATG) and equine antithymocyte globulin (eATG) are purified, pasteurized preparation of lymphocyte depleting polyclonal gamma immunoglobulin (IgG) raised against human thymus lymphocytes in rabbits and horses, respectively. They are used in prevention and/ or treatment of renal transplant rejection worldwide. 1e7

History of antibody use. rATG induction in combination with immunosuppressive therapy is more effective in preventing episodes of acute renal graft rejection in adult renal transplant recipients, in recurrent episodes of acute rejection, 8, 9 and those acute rejections that are not responsive to high-dose corticosteroid therapy than other monoclonal antibody preparations. 10,11 rATG recipients had a lower incidence of biopsy-confirmed acute rejection episodes, 12 greater event-free survival up to 10 years posttransplantation, and greater graft survival up to 5 years posttransplantation. 13 Mechanisms of action. The exact mechanism of these polyclonal antibodies has not been fully understood. 3,4,14e20 However, being polyclonal, they display specificity toward a wide variety of surface antigens (Ags) expressed on T and B-lymphocytes, dendritic cells, natural killer (NK) cells, and endothelial cells. However, T-cell depletion is considered to play a key role by modulating the expression of lymphocyte surface antigens involved in a wide variety of functions such as T-cell activation to endothelial adherence, activation of certain transcription factors, and interference with numerous immune cell processes, such as cytokine production, chemotaxis, endocytosis, cell stimulation, and proliferation. 14e20 In vitro studies indicate that binding of eATG to cells is generally nonspecific; the drug binds to visceral tissues, including thymus and testis cell membranes and nuclear and cytoplasmic components of tissues such as tonsil, kidney, and liver, 21 and is extensively bound to bone marrow cells, 22 and to other peripheral blood cells besides lymphocytes. 21 Diseases treated. As mentioned earlier, both antithymocyte globulins are used for treatment and prevention of acute renal allograft rejection. 2e8 More rATG recipients have been reported to achieve the endpoint of successful response (return of serum creatinine levels to baseline by end of treatment or within 14 days of treatment initiation). However, among those who achieved a successful response, fewer episodes of recurrent rejection occurred with rATG within 90 days of treatment cessation. 2 eATG is also used for treating moderate-tosevere aplastic anemia in patients who are unsuitable for bone marrow transplantation. 3, 23, 24 Adverse effects. The most common adverse effects are fever, thrombocytopenia, leukopenia, gastrointestinal disorders, and/or concurrent infection. 1, 2 Cytomegalovirus (CMV) infection was generally higher with rATG except in high-risk patients. 1, 25 eATG therapy may result in reactivation of or infection with CMV, herpes simplex virus, 25 or EpsteineBarr virus. 26 The incidence of malignancies is generally lower with rATG therapy. 27 This product is made of equine and human blood components, so it may carry a risk of transmitting infectious agents such as viruses, and theoretically, the CreutzfeldteJakob disease (CJD) agent.

Update. There has been recent evidence that the addition of human anti-T-lymphocyte globulin (ATLG) plus cyclosporine and methotrexate to standard graftversus-host disease (GVHD) prophylaxis is preferred over standard GVHD prophylaxis alone because it improves the probability of survival without relapse and of chronic GVHD after myeloablative peripheral blood stem-cell transplantation from a human leukocyte antigen (HLA)-identical sibling donor for patients with acute leukemia in remission. Additionally, this therapy provides better quality of life and shorter immunosuppressive treatment compared to standard GVHD prophylaxis without ATLG. 22 Antitoxin and Immune Globulins: Disease Modifying Tetanus immune globulin/Baytet/Hypertet Description. Tetanus immune globulin (TIG) is a specific solvent-detergent-treated plasma-derived product obtained from donors immunized with tetanus toxoid. TIG contains tetanus antitoxin that provides temporary passive immunity to individuals who have low or no immunity to the toxin produced by Clostridium tetani. 28, 29 Mechanisms of action. TIG contains tetanus antitoxin antibodies, which neutralize the free form of the powerful exotoxin produced by Clostridium tetani. 28, 30 TIG can only neutralize unbound exotoxin; it does not affect toxin already bound to nerve endings. 31 Diseases treated. TIG is used to provide passive immunity to tetanus as part of a postexposure prophylaxis regimen following an injury in patients whose immunization is incomplete or uncertain or if it has been more than 10 years since last dose of tetanus toxoid. 1,3e9 Adverse reaction. Slight soreness at injection site, mild fever, and rarely sensitization to repeated injections of human immune globulin has been reported. 28 Antitoxin and Immune Globulins: Disease Modifying Cytomegalovirus immune Globulin/Cytogam Description. Cytomegalovirus immune globulin IV (CMV-IG) is a purified immune globulin (hyperimmune globulin) that contains immunoglobulin G (IgG) derived from pooled adult human plasma selected for high titers of anti-CMV antibodies. 32 Mechanisms of action. CMV-IG provides relatively high concentration of antibodies directed against CMV. It provides prophylaxis against CMV infection or disease in immunocompromised individuals. 32e43 Results from in vitro studies and mice indicate that anti-CMV antibodies can neutralize the pathogenic properties of CMV. 42e44 As CMV usually targets a population of bone marrow-derived myeloid lineage progenitor cells, antibody-neutralization of the virus alone may not be enough to prevent or make active disease less severe in already CMV-infected individuals. 42,44e47 Disease treated. CMV-IG provides passive immunity to individuals who are at risk for primary CMV infection/disease, or secondary CMV disease (reactivation of CMV). 41,42,44e46,48e51 It is also prescribed for the prophylaxis of CMV disease associated with transplantation of kidney, lung, liver, pancreas, and heart. With the exception of CMVseronegative recipients of kidneys from CMVseropositive donors, CMV-IG prophylaxis should be considered in conjunction with ganciclovir.

Adverse reactions. Most frequent adverse reactions reported are flushing, chills, muscle cramps, back pain, fever, nausea, vomiting, arthralgia, and wheezing. 32,34e36 There is a slight risk of hemolysis, as intravenous immunoglobulin (IVIG) products can contain blood group antibodies, which may act as a hemolysin and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction. Transfusion-related acute lung injury (noncardiogenic pulmonary edema) and thrombotic events have been reported in patients receiving IVIG preparations. 32 Similar to all other products made from human plasma, this CMV-IG also carries the possibility for transmission of blood-borne viral agents and the CJD agent. However, this IVIG is treated with a solvent detergent viral inactivation procedure to inactivate a wide spectrum of lipid-enveloped viruses, including HIV-1, HIV-2, Hepatitis B, and Hepatitis C.

Antivenin [latrodectus mactans]/black widow spider antivenindantivenin Micrurus fulvius/eastern and Texas coral snake antivenindcrotalidae polyvalent immune Fab/Crofab Description. These antivenins are sterile, nonpyrogenic, purified, and lyophilized preparation of specific venom-neutralizing serum globulins obtained from the blood serum of healthy horses exposed to the venom of black widow spiders and eastern coral snake (Micrurus fulvius) venom, respectively. 52e55 In contrast, crofab is an antivenin made up of ovine Fab (monovalent) immunoglobulin fragments obtained from blood of healthy sheep immunized with North American Crotalinae subfamily of venomous snakes that includes rattlesnakes, copperheads, cottonmouth, or water moccasins. 56 Mechanisms of action. Mode of action of these antivenins is unknown. 52 However, they probably act by neutralizing venom of black widow spiders and coral snakes. 54 Crofab is a venom-specific Fab fragment of IgG that works by binding and neutralizing venom toxins, facilitating their redistribution away from target tissues and their elimination from the body. 56 Disease treated. These antivenins are indicated for patients with symptoms due to bites by black widow spider (Latrodectus mactans) 52 and bites of two genera of coral snakes, that is, Micrurus (including the eastern and Texas varieties) and Micruroides (the Sonoran or Arizona variety), found in southeastern Arizona and southwestern New Mexico. 52,57e59 Antivenin Micrurus fulvius (equine origin) is indicated only for treatment and management of adult and pediatric patients exposed to North American crotalid envenomation. 54 Adverse effects. Immediate systemic reactions (allergic reactions or anaphylaxis) and death can occur in patients sensitive to antivenin from horse serum. 52, 60 Most common adverse reactions to crofab are urticaria, rash, nausea, pruritus, and back pain. 61, 62 High antibody titer influenza fresh frozen plasma Description. Use of convalescent (persons who have recovered from a particular infection) donor plasma with high hemagglutination inhibition titer against certain influenza strains has been recommended as a primary therapy for severe respiratory infectious diseases including influenza, severe acute respiratory syndrome, and Middle East respiratory syndrome. 63 History of antibody use. A meta-analysis of previous cohort studies during the 1918 influenza pandemic showed a case-fatality rate of 16% among subjects treated with plasma, serum, or whole blood compared to 37% among controls. Similarly, in 2009, a cohort study using convalescent plasma for the treatment of pandemic H1N1 influenza resulted in a mortality of 20% in the treatment group versus 54% in the control group. 64 Mechanisms of action. Antiinfluenza convalescent plasma decreases the rate of viral shedding measured by neutralizing antibody titer and hemagglutination inhibition. 65 Both preexisting immunity (previous infections and vaccinations) as well as any immune response occurring after illness onset makes this mechanism of action more complex.

Disease classifications treated. Influenza, severe acute respiratory syndrome, and Middle East respiratory syndrome. 63 Adverse effects. Convalescent plasma seems safe. The serious adverse events reported are related to the underlying influenza, its complications, preexisting comorbidities, and not due to the convalescent plasma usage.

Description. Antibodies to the Ebola virus (EV) in whole blood or plasma from convalescent donors may be effective in the treatment of EV infection.

History of antibody use. The World Health Organization (WHO) has stated that convalescent blood or plasma is an option in the treatment of Ebola. 66 In 1999, transfusion of locally collected convalescent blood helped to decrease Ebola mortality. 67 Therefore, WHO has recommended the collection of convalescent plasma to treat patients with Ebola virus infection.

Mechanisms of action. This fresh frozen plasma (FFP) has high titers of antibodies directed against Ebola virus. 68 Adverse effects. Convalescent plasma seems safe with few adverse effects. 69, 70 Digoxin immune Fab/DigiFab; Digibind Description. Digoxin immune Fab is a sterile, purified, lyophilized monovalent preparation of bovine immunoglobulin Fab fragments that binds to digoxin. These Fab fragments are obtained from the blood of healthy sheep immunized with a digoxin derivative, digoxindicarboxymethoxylamine, a digoxin analogue that contains the functionally essential cyclopentaperhydrophenanthrene: lactone ring moiety coupled to keyhole limpet hemocyanin. The final product is prepared by taking the immunoglobulin fraction of the ovine serum, digesting it with papain, and isolating the digoxin-specific Fab fragments by affinity chromatography. 71e79

Mechanisms of action. DigiFab or Digibind have antigen-binding fragments that bind to free digoxin molecules that results in an equilibrium shift away from binding to receptors, thereby reversing the cardiotoxic effects of the glycoside. 71,72,75,76,78,80e87 Subsequently, Fab-digoxin complexes are cleared by the kidney and reticuloendothelial system. Due to papain treatment, the Fab fragments lack the antigenic determinants of the Fc fragment resulting in reduced immunogenicity to patients as opposed to intact immunoglobulin products. 71, 72, 75, 76, 78, 79, 84, 88, 89 Diseases treated. Digoxin immune Fab is indicated for patients with either life-threatening or potentially life-threatening digoxin toxicity or overdose. 71,79,90e95 Data from clinical trials have showed that both DigiFab and Digibind reduce levels of free digoxin in the serum to below the limit of assay quantitation for several hours after Fab administration.

Adverse reactions. Digoxin immune Fab (ovine) generally is well tolerated following intravenous (IV) administration. 71e73, 76, 78 Hypokalemia may occur, sometimes developing rapidly in patients receiving digoxin immune Fab (ovine). 71, 72, 79, 96, 97 DigiFab should not be administered to patients with a known history of hypersensitivity to papaya or papain unless the benefits outweigh the risks.

Immune Globulins: Antiinfectious Hepatitis B immune globulin/HepaGam B/nabi-HB/BayHepB/HyperHEP B S/D Description. Hepatitis B immune globulin (HBIG) is a specific immune globulin (hyperimmune globulin) that contains antibody to hepatitis B surface antigen (anti-HBs) prepared from plasma of healthy donors with high titer (>1:100,000) of anti-HBs antibody. It provides temporary passive immunity against hepatitis B virus (HBV). 98e104 HepaGam-B is a solvent/detergent-treated sterile solution of purified gamma globulin containing antibody to HBs antigen that contains high titers of anti-HBs from plasma donated by healthy screened donors. Both HBIG and HepaGam-B are manufactured by a solvent/detergent (S/D) treatment procedure that is effective in inactivating lipid-enveloped viruses such as hepatitis B virus, hepatitis C virus, and human immunodeficiency virus type 1 and type 2. However, S/D is less effective against nonlipid-enveloped viruses such as hepatitis A virus and parvovirus B-19. 100, 101, 104 Mechanisms of action. It provides passive immunization for individuals exposed to the hepatitis B virus by binding to the surface antigen and reducing rate of hepatitis B infection.

Diseases treated. HBIG provides passive prophylactic immunity to HBV infection for prevention of perinatal HBV infection in neonates born to HBs antigenpositive (HBsAg-positive) mothers, 100e106 for postexposure prophylaxis in susceptible individuals exposed to HBV or HBsAg-positive materials (e.g., blood, plasma, serum), 100e104,107e109 sexual exposure to HBsAg-positive persons, for household exposure to persons with acute HBV infection, and for prevention of HBV recurrence in liver transplant recipients who are HBsAg-positive (HepaGam-B only). 104,110e117 HBIG is not indicated for treatment of active hepatitis B infection and is ineffective in the treatment of chronic active hepatitis B infection. 105 Adverse reactions. The local adverse reactions that may occur at the site of injection after intramuscular (IM) administration are pain, tenderness, swelling, and erythema. 100, 101, 109 The systemic effects that may occur after IM administration are urticaria, angioedema, nausea, vomiting, myalgia, headache, fluor cold-like symptoms, lightheadedness, and malaise have been reported. 100, 101, 104 Varicella zoster immune globulin/VariZIG Summary. Varicella zoster immune globulin (VZIG) is a specific immune globulin (hyperimmune globulin). VZIG is prepared from plasma of donors selected for high titers of antibodies to varicella zoster virus (anti-VZV) and used to provide temporary passive immunity against VZV. 118e120

Mechanisms of action. VZIG acts by neutralizing varicella zoster virus via high titers of IgG antibodies present in the plasma used.

Diseases treated. VZIG is used for postexposure prophylaxis of varicella (chickenpox) in individuals who do not have evidence of varicella immunity and are at high risk for severe varicella infection and its complications. These high risk individuals include immunocompromised patients such as neonates whose mothers have signs and symptoms of varicella around the time of delivery (i.e., 5 days before to 2 days after), premature infants born at !28 weeks of gestation who are exposed during the neonatal period and whose mothers do not have evidence of immunity, premature infants born at <28 weeks of gestation or who weigh 1000 g at birth and were exposed during the neonatal period regardless of their mothers' evidence of immunity status, and finally pregnant women. 118, 119, 121, 122 VZIG is now recommended for outbreak control and postexposure treatment, and the vaccine is available to children with humoral immunodeficiencies and selected children with HIV infection. 122 Use of VZIG for postexposure prophylaxis in pregnant women exposed to VZV may prevent or reduce severity of varicella in the woman but does not prevent fetal infection. 119, 121 VZIG is not indicated for individuals who previously received age-appropriate varicella vaccination and subsequently became immunocompromised because of disease or immunosuppressive therapy later in life. Bone marrow transplant recipients should be considered susceptible to varicella regardless of previous history of varicella or varicella vaccination in themselves or their donors. However, those who develop varicella or herpes zoster after transplantation should be considered immune to varicella. 119 Adverse reactions. The most common adverse effects reported with VZIG in clinical trials in pregnant women, infants, and immunocompromised adults and children were injection site pain, headache, chills, fatigue, rash, and nausea. Severe hypersensitivity reactions may occur following administration of VZIG. 118 

Summary. Rimabotulinumtoxin B, a type B botulinum toxin produced by fermentation of the bacterium Clostridium botulinum type B (Bean strain), is a neuromuscular blocking agent (neurotoxin) and inhibitor of acetylcholine release at motor nerve terminals. 123e126

Mechanisms of action. Rimabotulinumtoxin B and other botulinum toxin serotypes act by inhibiting acetylcholine release at the neuromuscular junction via a three-step process, that is, toxin binding, toxin internalization, and inhibition of acetylcholine release into the neuromuscular junction leading to chemical denervation and flaccid paralysis. 123, 124, 126, 127 Diseases treated. Rimabotulinumtoxin B is used for management of adults with cervical dystonia (also called as spasmodic torticollis) to reduce severity of abnormal head positioning and neck pain through reduction of undesired or excessive contraction of striated or smooth (involuntary) muscle. 128e131

Adverse reactions. The most common adverse effects reported with Botulinum toxin are dry mouth, dysphagia, dyspepsia, and injection site pain. 123,132e134 Serious hypersensitivity reactions have been rarely reported with onabotulinumtoxin A. 127

Summary. Botulism immune globulin IV (BIG-IV) is a specific immune globulin (hyperimmune globulin) that is prepared from plasma of adult volunteer donors immunized with pentavalent botulinum toxoid, which neutralizes free botulinum toxin types A and B. It is one of the most poisonous substances known and exists in seven antigenic variants (types A to G). 120, 121, 135 Mechanisms of action. BIG-IV is a human-derived antitoxin that neutralizes botulinum toxin. BIG-IV has a half-life of approximately 28 days in vivo and large capacity to neutralize the toxin. 135 Disease treated. Infant botulism occurs when young infants ingest spores of Clostridium botulinum that then germinate, colonize the GI tract, and produce botulinum toxin. This neurotoxin causes generalized weakness and loss of muscle tone. A single infusion will neutralize the toxin for at least 6 months and toxins type A or B that may be absorbed from the colon of an infant younger than 1 year old. 121,135e139 Adverse effect. Mild, transient, blush-like erythematous rash on the face or trunk occurred in 9% e14% of infants receiving BIG-IV in clinical studies. 135, 140 Rabies immune globulin/bayrab/HyperRAB, imogam Rabies, KedRAB Description. Rabies immune globulin (RIG) is a sterile solution of specific IgG that contains antibody to rabies antigen. It is used to provide temporary passive immunity to rabies infection as part of a postexposure prophylaxis regimen in unvaccinated individuals exposed to the disease or virus. 141e144

Mechanisms of action. RIG is a human-derived antitoxin that neutralizes rabies virus so that virus spread is reduced and its infective or pathogenic properties are inhibited. Specific rabies antibodies present in RIG neutralizes rabies. It should be used in conjunction with rabies vaccine and can be administered through the seventh day after the first dose of vaccine is given. RIG provides immediate, temporary rabies virus-neutralizing antibodies until the patient responds to active immunization and produces virus-neutralizing antibodies. 121,141e144 Diseases treated. Given to all persons suspected of exposure to rabies with one exception, those who have been previously immunized with rabies vaccine and have a confirmed adequate rabies antibody titer should receive only vaccine.

Adverse reactions. Most common local adverse effects include tenderness, pain, muscle soreness, or stiffness that may occur at the site of injection. Lowgrade fever, headache, and malaise may also occur. 141e143

Immune Globulins: Immunomodulation Rho(D) immune globulin/WinRho; RhoGam; Rhophylac, MicRhoGAM, BatRhoD, HyperRho Summary. Rho(D) immune globulin (RhIG) consists of anti-Rho(D) IgG antibodies to the red blood cell Rho(D) antigen. RhIG is prepared from human pools of plasma of Rho(D)-negative donors immunized with Rho(D)-positive red blood cells after cold alcohol fractionation, and subsequent purification and infectious disease reduction technologies. 145e150

Mechanisms of action. The exact mechanism of action of Rho(D) immune globulin in the suppression of formation of anti-Rho(D) is not fully known.

In the treatment of preventing D alloimmunization, RhIG binds to Rho(D) antigen that entered the maternal circulation during fetalematernal hemorrhage (FMH) involving an Rho(D)-positive fetus or transfusion with Rho(D)-positive blood, preventing stimulation of the mother's primary immune response to Rho(D) antigen. Therefore, by preventing the active production of anti-Rho (D) by the mother, the risk of hemolytic disease of the fetus and newborn in future pregnancies is decreased. 145e149 In the treatment of idiopathic thrombocytopenic purpura (ITP), administration of Rho(D) immune globulin to Rho(D)-positive individuals is believed to cause transient mononuclear macrophage Fc receptor (FcR) blockade by complexes within the reticuloendothelial system, particularly the spleen, which spares the patient's IgG-coated platelets. This FcR blockade and decreased Fc-mediated phagocytosis of antibodycoated platelets result in increases of platelet counts in ITP patients. 145,149,151e156 Diseases treated. Prevent D alloimmunization in Dnegative women of childbearing potential if the neonate is D þ , weak-D positive, or D untested, and following perinatal events associated with FMH such as abortion, ectopic pregnancy, amniocentesis, chorionic villus sampling, external cephalic version, abdominal trauma, and antepartum hemorrhage. It is also used to prevent D alloimmunization in Dnegative individuals who receive D þ blood components such as whole blood-derived platelets, apheresis platelets, and/or granulocytes. Similarly, it is used for the treatment of ITP in D þ patients who had not undergone splenectomy. 145e147,149,151e153,157e164 Some preparations of Rho(D) immune globulin may be administered IM or IV (Rhophylac, WinRho SDF), whereas others are labeled for IM use only (MICRhoGAM, RhoGAM, HyperRHO S/D Full Dose, HyperRHO S/D Mini-Dose). 145e147,149,165 When used for ITP treatment, RhIG must be administered IV. 145, 149 Adverse reactions. Generally, mild with the most common being headache, fever, chills, pain at the injection site and, rarely, hypersensitivity reactions. Some degree of hemolysis is inevitable, but this is predictable and transient. 146, 147 Immunoglobulin (generic)/bbrands: Bivigam, Carimune, Cuvitru, Flebogamma, Gammagard, GamaSTAN, Gammaked, Gammaplex, Gamunex-C, Hizentra, Hyqvia, Octagam Privigen Summary. Immune globulin IM (IMIG), immune globulin IV (IVIG), and immune globulin subcutaneous are sterile, nonpyrogenic preparations of globulins containing many antibodies normally present in adult human blood. Immune globulins (IG) are collected either by whole blood donations as recovered plasma (20%), or by apheresis as source plasma (80%). IVIG is a highly purified product consisting mostly of IgG with a half-life of 21e28 days.

Hyperimmune globulin (Hyper-Ig) products are manufactured from donors with high Ig titers with specificity to antigenic determinant(s) of interest. High titers of these donors can be achieved by natural immunity, prophylactic immunizations, or through targeted immunizations. Hyper-Ig products should contain at least fivefold-increased titers compared to standard preparations of IVIG. IVIG production is regulated by the IUIS/WHO (International Union of Immunological Societies/World Health Organization), which require the following:

• Source material must be plasma obtained from a minimum pool of 10,000 donors; • Product must be free of prekallikrein activator, kinins, plasmin, preservatives, or other potentially harmful contaminants; • IgA content and IgG aggregate levels need to be as low as possible; • Product must contain at least 90% intact IgG; • IgG should maintain opsonin activity, complement binding, and other biological activities; • IgG subclasses should be present in similar proportions to those in normal pooled plasma; • Antibody levels against at least two species of bacteria (or toxins) and two viruses should be determined; • Product must demonstrate at least 0.1 international units of hepatitis B antibody per mL, and hepatitis A radioimmunoassay titer of at least 1:1000; • Manufacturer should specify the contents of the final product, including the diluent and other additives, and any chemical modification of IgG. 166e172

Mechanisms of action. The mechanisms of Ig-induced immunomodulation are incompletely understood but include macrophage Fc receptor blockage by immune complexes formed between IVIG and native antibodies, modulation of complement, suppression of antibody production, suppression of inflammatory cytokines and chemokines, and/or antiidiotypic regulation of autoreactive B-lymphocytes or antibodies. As IVIG contains a diverse group of antibody specificities, which protects recipients against multiple infections by eliminating opsonized infectious organisms via antibody-dependent cell-mediated cytotoxicity or by complement activation. This is followed by lysis and/ or neutralization of soluble infectious proteins by immune complex formation and elimination through the RES. 166,170,173e175 Diseases treated. IVIG is indicated for the treatment of primary immune deficiency, secondary immune deficiency, ITP, Kawasaki disease, and congenital hypogammaglobulinemia. Currently, there is an extensive list of diseases for which IVIG could be used. It also has immunomodulatory properties resulting in an increasing list of both FDA-approved and nonapproved indications.

IMIG is used to provide passive immunity to hepatitis A virus infection for preexposure or postexposure prophylaxis in susceptible individuals who are at risk of or have been exposed to the virus. IMIG and IVIG are used to prevent or modify symptoms of measles (rubeola) in susceptible individuals exposed to the disease <6 days. IVIG is used for replacement therapy to promote passive immunity in patients with primary humoral immunodeficiency who are unable to produce sufficient amounts of IgG antibodies and in the management of ITP to increase platelet counts, to prevent and/or control bleeding, or to allow these patients to undergo surgery.

IVIG is used for prevention of bacterial infections in patients with hypogammaglobulinemia and/or recurrent bacterial infections associated with B-cell Chronic Lymphocytic Leukemia. IVIG is used in conjunction with aspirin therapy for initial treatment of the acute phase of Kawasaki disease. IVIG is also used to treat chronic inflammatory demyelinating polyneuropathy to improve neuromuscular disability and impairment, and for maintenance therapy to prevent relapse. Furthermore, IVIG is used for maintenance treatment to improve muscle strength and disability in adults with multifocal motor neuropathy. 166e201

Adverse reactions. Approximately 2%e10% of infusions are associated with adverse reactions that include those at the infusion site (erythema, pain, swelling, pruritus, heat), phlebitis, eczema, fever, chills, myalgias, malaise, flushing, rash, diaphoresis, pruritus, bronchospasm, chest pain, back pain, extremity pain, dizziness, blood pressure changes, nausea, vomiting, and headache. 167,170,172,177e179,181e183 

In the late 20th century (w1986), monoclonal antibodies were developed. The first monoclonal antibodies (Mabs) were of xenographic source and were wrought with problems of immunogenicity. These early Mabs did not gain favor until chimerization took pace in the mid-1990s, and in 1998 two Mabs were approved to treat one respiratory syncytial virus and the other certain breast cancers. Further development to humanize and then generate fully human Mab led to an evolution of therapies utilizing these agents. Mabs are being researched or approved to treat a multitude of diseases that include oncologic, inflammatory, autoimmune, cardiovascular, respiratory, neurologic, allergic, benign hematologic, infectious, orthopedic, coagulopathic, and metabolic indications and to decrease disease morbidity (diminution of pain), modify disease progression (i.e., macular degeneration, diabetes), and potentially alter anatomic development. In this section of the chapter, we will review the history of use of these passive monospecific antibody therapies, their mechanism of action, pharmacologic-therapeutic classification, particular medical indication, adverse reactions, and potential future use of these medications. 201 

Depending on the antigenic target of these antibodies multiple events are set into action. Immunologic changes occur as the specific antigens are presented more efficiently to effector cells. Some of these actions create decreased inflammatory and allergic responses, while other effects generate antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Other actions can block receptor interaction with ligands by either binding with ligands or their cognate receptors (i.e., allow activation of NK cells). Interactions may also directly cause initiation of programmed cell death (apoptosis), cessation of growth/replication/proliferation, or lead to changes in metabolism. Moreover, there are also antibodies against infectious agents to prevent cell adhesion for entry, spread, replication, and contagion. Antibodies may also be directed against toxins leading to various methods of inactivation. 201 

Depending on their mode of action, Mabs are associated with a myriad of side effects. They can be associated with immunogenicity that can cause a decrease in their effectiveness. Antineoplastic antibodies can be associated with tumor lysis syndrome. Similarly, reactivation of underlying infections can occur leading to progressive multifocal leukoencephalopathy, HBV, fungal, parasitic, or tuberculosis infections. Other adverse reactions include but are not limited to initiation of autoimmune disorders, increased risk for malignancy, cardiac arrhythmia, angina/ischemia, cytopenias, hemorrhage, and allergic reactions including anaphylaxis, embryoefetal toxicity (if can cross placental barrier), and even death.

Malignancies can be caused by infectious agents, toxins, or genetic mutations with changes in control of growth, proliferation, or programmed cell death. Historically these have been treated with a variety of radiation therapies to eradicate malignant cells or with chemotherapeutic agents to enhance maturity, decrease proliferation, or cause destruction of cancer cells. In some cases intense high-dose chemotherapy is used to cause cancer remission with stem cell transplants for subsequent rescue. Passive antibody therapy may replace or be additive to other pharmacology therapies and increase chances for complete remission, prolong disease-free survival, and overall survival.

Rituximab (Rituxan) is a chimeric murine/human Mab (IgG1k) that binds to CD20 (human B-lymphocyterestricted differentiation antigen, Bp35 {controlling differentiation and possible calcium ion channel}). Its mechanism of action is not entirely clear and may involve CDC and ADCC. Many studies have shown this antibody to have an additive benefit to standard chemotherapy alone. This antibody has been approved by the FDA to treat chronic lymphocytic leukemia (CLL) since 1997. Nowadays, this medication is often combined with ibritumomab in treating CLL (to be discussed with non-Hodgkin's lymphoma). 202, 203 Alemtuzumab (Campath) binds to CD52 and is a humanized rat Mab (IgG1k) binding to receptors on both T and B cells as well as macrophages, NK cells, and neutrophils, leading to CDC and ADCC. The resultant cytopenias lead to a severe immunocompromised state. Alemtuzumab was FDA approved as a single agent in the treatment of B-cell CLL in 2001. 204 Ofatumumab (Ocrevus) is a human Mab (IgG1k) with CDC that binds to CD20 near the cellular membrane. In phase II studies, this agent had 86% objective response rate (ORR) when used alone and with CHOP therapy had 100% ORR and 62% complete remission (CR); whereas, in phase III trials, this Mab showed ORR of 10% after rituximab relapse. This medication was approved by the FDA to treat CLL in 2009. 205 Monalizumab is a humanized Mab (IgG4k) that binds to CD94/NKG2A (an inhibitory signal receptor transmitter) on NK cells. Monalizumab demonstrated blockade of NKG2A/HLA-E and restores the ability of NK cells to lyse B cells in vitro. In addition, this Mab was shown to be of benefit in murine models. Ongoing phase I/II studies will be completed in 2019. 206 Otlertuzumab is a humanized Mab fragment (IgG Fab') with specificity to CD37 that induces both ADCC and caspase-independent apoptosis. In a phase II study both better progression-free survival (PFS) and ORR were observed when used with bendamustine compared to bendamustine used alone. 207 Urelumab is a human Mab (IgG4k) with specificity to CD134 (an immune checkpoint inhibitor). This antibody has completed safety phase I dosing trials. Higher doses lead to significant hepatotoxicity. Safe dosing is now established in clinical phase II studies to be completed in 2020. 208, 209 Ulocuplumab is a human Mab with specificity to CD184 (CXCR4). In vitro studies showed apoptotic effects via production of oxygen species that was not associated with better caspase activation than AMD3100. Phase I studies were completed in 2014, no manuscripts were found for review. This medication is presently in phase II trials against acute myelocytic leukemia (AML) to be completed in 2021. 210, 211 Other monoclonal antibodies not demonstrating benefit in clinical trials for CLL include apolizumab, dacetuzumab, and gomiliximab (aka lumiliximab) 212e215

Acute myelocytic leukemia AML is the leading cause of leukemic mortality in the United States (US). Over the last 10 years therapy has not changed significantly for this disease. Novel therapies have been developed in the last decade, some showing temporal success and some showing a brighter tomorrow. 216 AMG330 is a bispecific T-cell engager (BiTE) antibody with specificity for CD3 and CD33. This Mab is currently in clinical trials to be completed in 2020 for treatment of AML. A BiTE antibody stimulates ADCC (via T cells) in the presence of antigenic targets on cells of interest. In vitro studies have shown effective lysis of AML cells, while in animal studies it has demonstrated significant decrease in tumor burden. 217 IMGN632 is an anti-CD123 antibody complexed to a DNA mono-alkylating agent. In vitro studies showed it had more potency against AML cells than to normal myeloid progenitor cells. In animal models there was an excellent response rate against tumor cells. Ongoing clinical trials will be completed in 2021. 216 Talacotuzumab is a humanized monoclonal antibody (IgG1-2k) with specificity to interleukin (IL)-3 receptor subunit-a (CD123, a growth and differentiating receptor). This antibody induces ADCC both in vitro and in animal models. Phase III clinical trials were reportedly completed in 2018; published results are forthcoming. 218 Samalizumab is a humanized Mab (IgG2/IgG4k) with specificity to CD200 (OX-2membrane glycoprotein) is in phase II trials to be completed in 2021. 219 Ficlatuzumab is a humanized Mab (IgG1k) in a phase I trial to treat refractory/relapsing AML to be completed in 2020. 220 Other Mab not demonstrating benefit in clinical trials or withdrawn following postmarketing for AML include gemtuzumab ozogamicin (FDA approved 2000 withdrawn 2010 secondary to venoocclusive disease) and lintuzumab (no added benefit over standard chemotherapy). 221e223

Daratumumab (Darzalex) is a human Mab (IgG1k) with specificity to CD38 (functions reportedly include receptor-mediated adhesion and signaling events, as well as important bifunctional ectoenzymatic activities that contribute to intracellular calcium mobilization. This Mab mechanism of action is thought to induce CDC, ADCC, antibody-dependent cellular phagocytosis, and apoptosis. This medication is used to treat refractory and recurrent multiple myeloma. 224, 225 Silutuximab (Sylvant) is a chimeric Mab (IgG1k) with specificity to IL-6. This medication was FDA approved in 2014 for multicentric Castleman's disease (MCD) with HIV negative and HHV-8 negative. There are ongoing studies in phase II clinical trials to be completed in 2019. 226, 227 B-cell acute lymphoblastic leukemia (B-cell ALL) Blinatumomab (Blincyto) is a mouse double heavychain fragment (Murine {scFv -kappa e heavy} e {scFv -heavy e kappa}) with specificity for CD19 and CD3 known as a BiTE. This Mab's mode of action is by directing CD3 þ effector memory T cells to CD19 þ target cells leading to T-cell activation and B-cell apoptosis. This biologic is used to treat relapsed/refractory cell ALL. In phase III trials event-free survival almost tripled and duration of remission almost doubled. 228e230

Hodgkin's lymphoma is a rare malignancy affecting young adults with a peak incidence in patients >55 years old. Up to 40% of these patients can develop relapsing disease. Brentuximab vedotin (Adcentrix) is a chimeric humanized Mab drug conjugate (Mab þ linker þ payload {IgG1k þprotease cleavage linker þ monomethyl auristatin E [MMAE]}) with specificity to CD30 (a cell membrane protein of the tumor necrosis factor receptor superfamily member 8. MMAE is a microtubule-disrupting agent. The combination of this a Mab and drug conjugate disrupts the intracellular microtubule network causing cell cycle arrest at G2/M stage and apoptosis. This medication has a 43% PFS at 30 months. 231 Mab to look out for in the future include Camidanlumab tesirine (ADCT-301) a human Mab (IgG1k). This Mab has specificity to CD25 (a IL-2 receptor alpha subunit) with a drug conjugate. The drug is released intracellularly and causes DNA interstrand crosslinks. This Mab is in phase I studies to be completed in 2019 for Hodgkin's and non-Hodgkin's T-and B-cell lymphomas. In addition, there are clinical phase I studies against multiple solid tumors to be completed in 2021. 232, 233 Agents abandoned or not found to be beneficial include apolizumab, denintuzumab mafodotin (HBU-12), iratumumab (MDX060), and lucatumumab (HCD122). 212, 234, 235 Anaplastic large cell lymphoma Brentuximab vedotin (Adcentrix) is an FDA-approved medication for patients with refractory or relapsed anaplastic large cell lymphoma who achieved CR. This Mab had 79% OS and 57% PFS at 5 years, with median response duration not reached at time of publication. 236 

Atezolizumab (Tecentriq) is an FcgR bindingedeficient, fully humanized Mab (IgG1k). This Mab binds to programmed death ligand I (PD-L1) to prevent interaction with receptors PD-1 and B7.1 (a costimulatory cellsurface protein), reversing T-cell suppression. Activation of B7.1 can potentially stimulate long-term responses through development of new immunity via priming and activation of T cells in lymph nodes. A lack of FcgR binding decreases ADCC of the T cells enabling more tumor-specific T cell to remain active. This medication was approved by the FDA in 2019 to treat triple negative (estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2) unresectable or metastatic breast cancers. 237, 238 Colorectal Cancer Bevacizumab (Avastin) is a humanized Mab (IgG1k) with specificity to vascular endothelial growth factor-a (VEGF-A) that acts as an inhibitor of angiogenesis. It was FDA approved for treatment of colorectal cancer and has recently been approved for multiple other cancers including ovarian, fallopian cancers, renal cell carcinoma, and recurrent glioblastoma multiforme (GBM). 239, 240 Urothelial Carcinoma Atezolizumab (Tecentriq) is FDA approved as a single agent in urothelial carcinoma and for patients with disease progression despite other chemotherapy treatment. 241, 242 Nonsmall cell lung cancer Atezolizumab (Tecentriq) is FDA approved as a single agent for nonsmall cell lung cancer (NSCLC).

Bevacizumab (Avastin) is FDA approved for treatment of locally advanced, recurrent or metastatic, nonsquamous NSCLC.

Nivolumab (Opdivo) is an FDA-approved human Mab (IgG4k) immunoglobulin and blocks PD-1 preventing interaction PD-1 and its ligands PD-L1 and PD-L2. It is used to treat RCC, NSCLC, Hodgkin's lymphoma, melanoma, small cell lung cancer, colorectal cancer, and squamous cell carcinoma of the head and neck. In phase III clinical trials, nivolumab performed better than docetaxel in the treatment of NSCLC. 243e245

Ovarian/cervical fallopian cancer Bevacizumab (Avastin) is FDA approved for treatment of locally advanced, recurrent or metastatic, ovarian, cervical, and fallopian cancers after treatment with chemotherapy regimens and surgery. 246 

Merkel cell carcinoma is a rare aggressive cutaneous malignancy caused by infection with polyoma virus and exposure to ultraviolet radiation. This cancer was classically treated with chemotherapeutic agents leading to rare durable responses. Avelumab (Bavencio) is a fully human Mab (IgG1l) with specificity to PD-L1. This Mab was approved by the FDA for treatment of Merkel cell carcinoma in 2017. Treatment with this Mab increases response rates to about 50% and extended durable response times approximately five times. 247, 248 This Mab is in clinical trial to treat other solid tumors including but not limited to hepatocellular, ovarian, esophagogastric, colorectal NSCLC, testicular, urothelial, and adrenocortical carcinomas. 249 Neuroblastoma Neuroblastoma is an aggressive tumor of children with a 5-year survival of about 50%. Treatment classically is high-dose intensive chemotherapy, myeloablative chemotherapy with stem cell rescue, and/or irradiation therapy. Dinutuximab (Unituxin) is a chimeric Mab (IgG1k) with specificity to GD2 ganglioside that has mechanisms of action via CDC and ADCC. This Mab is used in patients who have had at least a partial response to classic therapy. 250, 251 Glioblastoma Multiforme GBM is the most common malignant primary brain tumor in adults. This disease remains incurable.

Bevacizumab (Avastin) is FDA approved for treatment of recurrent GBM as salvage therapy. This medication with chemotherapy increases overall survival by 4 months but as a single agent is not effective. 252 Relatlimab (BMS-986,016) is a human Mab (IgG4k) with specificity to lymphocyte activation gene 3 (LAG3, CD223) and is in phase I clinical trials to be completed in 2020 for treatment of GBM. 253 Tanibirumab (aka Olinvacimab, TTAC-0001) is a human Mab (IgG1) with specificity to vascular endothelial growth factor receptor-2 (VEFR-2) and is in phase II studies to treat GBM to be completed in 2020. 254e256

Catumaxomab (Removab) is a trifunctional rat/murine hybrid antibody (IgG2a/IgG2b). Catumaxomab consists of one "half" (one heavy chain and one light chain) of an antiepithelial cell adhesion molecule (anti-EpCAM) antibody and one-half of an anti-CD3 antibody, so that each molecule of catumaxomab can bind both EpCAM and CD3. In addition, the Fcregion can bind to an Fc receptor on accessory cells such as other antibodies, which has led to calling the drug a trifunctional antibody. This antibody's mechanism of action is through ADCC. It is approved for use in Europe for malignant ascites from ovarian, gastric, colon, pancreatic, breast, and endometrial carcinoma and is a pending review for approval by the FDA. 257e260

Cutaneous squamous cell carcinoma Cemiplimab (Libtayo) is a human Mab (IgG4) for treatment of cutaneous squamous cell carcinoma (CSCC) that is metastatic or locally advanced and not amenable to surgery. CSCC is second only to basal cell carcinoma as the most common skin cancer. Surgical intervention is not possible in 5% of patients. This Mab offers a treatment with less morbidity than palliative radiation or surgery, and gives an ORR in 50% of these otherwise untreatable patients. There are many additional phase II studies involving this Mab to be completed from 2020 to 23. 261,262

Inflammatory bowel disease (IBD) pathophysiology remains unknown but may have genetic, infectious, autoimmune origins including cell-mediated immunity. These diseases may be classified as ulcerative colitis (UC), isolated to the colon, or Crohn's disease primarily found in the colon but may involve the entire gastrointestinal tract. With long-standing active disease, malignancy is much more frequent in UC than in Crohn's disease. Mild UC is treated with antiinflammatory agents such as sulfasalazine and glucocorticosteroids. For more severe disease, high-dose steroids may be used to maintain disease quiescent and low-dose steroids to keep disease in remission. Low-dose chemotherapeutic agent or immunosuppressive agent may also be added if dose of corticosteroids is too high to maintain remission. Surgery may be necessary to control disease. For Crohn's disease, medical therapy is usually less successful in managing the disease and surgery may be necessary but is not curative as in UC. For both of these disease processes, passive antibody therapy may offer not only control of disease but possible complete remission from mucosal damage. 263, 264 Adalimumab (two formulations: Humira and Amjevita) is a recombinant human Mab (IgG1) with specificity to tumor necrosis factor alpha (TNF-a). Both forms are FDA approved to treat Crohn's disease as well as multiple types of rheumatoid arthritis. In Crohn's disease, this medication decreases signs and symptoms of disease and is able to induce clinical remissions. 265, 266 Certolizumab (Cimzia) is a recombinant humanized m fragment with TNF-a as target. It is FDA approved for both Crohn's disease and Rheumatoid arthritis. 267e269 Vedolizumab (Entyvio) is a humanized Mab (IgG1k) that has selectivity for integrin a4b7 and is FDA approved for treatment of Crohn's disease. This Mab mode of action is to selectively block trafficking of memory T cells into inflamed gut tissue by inhibiting a4b7-mucosal addressin cell adhesion molecule-1 (MAd-CAM-1) interaction with intestinal vasculature. This medication has shown a good safety profile with no cases of promyelocytic leukemia (PML), no increased risk of infections, malignancies compared with classically treated IBD, and low incidence of infusion-related reactions. This medication is also FDA approved for UC. 270, 271 Infliximab (Remicade, Inflectra, Remsira) is a chimeric Mab (IgG1k) with specificity to TNF-a and is FDA approved for IBD and multiple inflammatory arthritic diseases. This medication allows for steroid-free remission within months of starting therapy. 272 Natalizumab (Tysabri) is a humanized Mab (IgG2k) with selectivity to CD62L (L selectin a4 subunit of a4b1 and a4b7 integrins of leukocytes, not neutrophils, VLA-4). This Mab is FDA approved for Crohn's disease and multiple sclerosis. This medications is effective in induction of clinical remission in moderate-to-severe Crohn's disease. This medication does have the risk of PML. 273, 274 Other Mab being studied for Crohn's disease but not yet approved by the FDA include Ustekinumab, brazikumab, etrolizumab, risankizumab, and ontamalimab. In contrast, Mabs studied but not beneficial for Crohn's disease include andecaliximab, eldelumab, and fontolizumab. Refer to 

Mabs being studied for UC but not yet approved by the FDA include bimekizumab, etrolizumab, golimumab, mirikizumab, ravagalimab, sacituzumab govitecan, ontamalimab, and vatelizumab. Refer to 

Autoimmune diseases affect many organs and tissues including liver, gall bladder, pancreas (b islet cells in diabetes mellitus), nerve junctions (myasthenia gravis), thyroid, bone and joints, blood vessels, and multiorgan systems, systemic lupus erythematosus (SLE). Autoimmune arthritis is of multiple types including psoriatic, sclerosis, rheumatoid arthritis (RA), and SLE. Many of these diseases are mediated by antibody or cellular autoimmunity but ultimately appear to be secondary to an underlying abnormality in T-cell immuneregulatory control. These disease processes are historically controlled with antiinflammatory agents, immunosuppressive/immunomodulatory agents, or low-dose chemotherapy. Those with resultant hormone deficiencies are supplemented with hormones depleted by the disease process. It is hoped that passive antibody therapy will mitigate the sequelae of these inflammatory processes.

Psoriasis affects 2%e3% of the world population and is an inflammatory skin disease. Brodalumab (Siliz) is a human Mab (IgG2k) with specificity to IL-17 receptor A (IL-17RA). It is FDA approved for treatment of plaque psoriasis, and its mechanism of action is by inhibiting IL-17A, IL-17F, IL-17C, IL-25, and IL-17A/F heterodimer cytokine-induced responses including release of proinflammatory cytokines. When compared to ustekinumab, response rates nearly doubled with brodalumab in phase II and phase III trials during induction and maintenance therapies. 275, 276 Other therapies currently also approved or being studied for treatment of this disease include bermekimab (MABp1,T2-18C3, CA-18C3, Xilonix), bimekizumab, briakinumab, certolizumab pegol (Cimzia), etanercept (Enbrel), infliximab (Remicade, Inflectra, Remsima), itolizumab (Alzumab), adalimumab (Humira, Amjevita), ustekinumab (Stelara), secukinumab (AIN457, Cosentyx), guselkumab (Tremfya), tildrakizumab (MK-3222, SCH-900,222, Ilumya, Ilumetri), risankizumab (ABBV-066, BI-655,066), mirikizumab (LY3074828), namilumab (MT203), netakimab, and vunakizumab. Refer to Table 16 .1.

Withdrawn from market or ineffective for treating psoriasis include efalizumab (Raptiva), fezakinumab, bleselumab, and teplizumab (MGA031, PRV-031, hOKT3g1(Ala-Ala)) Refer to 

Abatacept (Orencia) is a recombinant soluble fusion protein of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc portion of human IgG1. Its mechanism of action is as selective costimulation modulator as it inhibits T lymphocyte activation by binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes. This medication is FDA approved for both juvenile idiopathic arthritis (JIA) and adult RA. 277e279

Certolizumab pegol alone or with methotrexate improves quality of life in RA and may cause disease remission and reduce joint damage. 280 

Certolizumab pegolis is also approved for use with ankylosing spondylitis.

Belimumab (Benlysta) is a human Mab (IgG1l) that binds to B-cell activating factor and acts as a Blymphocyte stimulator-specific inhibitor. It was approved by the FDA in 2011 for treatment of adult patients with active, autoantibody-positive SLE receiving standard therapy. This medication also decreases episodic frequency of lupus nephritis. 281e283

Despite marked improvement in survival from cardiovascular disease, this illness remains the number one cause of mortality in the US. This process causes injury to the endothelium of blood vessels of the heart secondary to toxins, accumulation of cholesterol, or chronic low-grade inflammation. Treatment has been preventive, primarily during actual injury or following injury. Therapies involve changes in behavior (diet, exercise, and cessation of tobacco use), pharmacologic to control contributing underlying illness (hypercholesterolemia, hypertension, diabetes type I and II), to diminish injury through thrombolytics, stents, vasodilators, supplemental oxygen, or to control sequelae of infarctions (cardiac dysfunction/failure). Passive antibody therapies are being tried to decrease the effects of some of the contributing factors of atherosclerotic plaque formation. Abciximab (ReoPro) is a chimeric recombinant monoclonal fragment (IgG1 Fab') with specificity to platelet glycoprotein IIb/IIIa receptor (CD41 7E3)/Intergrin a-IIb that prevents platelets from binding to fibrinogen. This Mab also prevents coagulation factor XIII from binding to platelets allowing stabilization of clots and are more easily lysed. The Fc portion of the antibody is removed to decrease thrombocytopenias. This antibody is used during high-risk coronary intervention to prevent clot formation and cardiac ischemia. 284 Alirocumab (Praluent) is a human Mab (IgG1) with specificity to proprotein convertase subtilisin/kexin type 9. This medication is used to control cholesterol levels in patients at high risk for cardiovascular events and in patients with familial hypercholesterolemia who are not controlled by other agents. 285e287 Evolocumab (Repatha) is a human Mab (IgG2l) FDA approved for the treatment of hypercholesterolemia in patients with familial hypercholesterolemia or history of cardiovascular disease. This Mab has specificity to PCSK9. This medication reduced low-density lipoprotein (LDL) and cholesterol levels by 60% even after statin therapy. Hazard ratios for primary and secondary endpoints were less than one (w0.80e0.85) with fewer cardiovascular-related death or infarction and stroke. 288, 289 Under future watch is frovocimab (LY3015014) a humanized Mab (IgG4k) with specificity to PCSK9 that completed phase I and II trials. There was up to 50% reduction in LDL cholesterol levels. Phase III studies have yet to be performed. 290 An additional antibody is lodelcizumab a humanized Mab (IgG1k); however, no studies were found in clinicaltrials.gov or in Pubmed searches.

Bococizumab is a humanized Mab (IgG2k) that was in phase III trial, which was discontinued secondary to primary endpoints not being achieved. 291 

Besides autoimmune and malignant diseases of the neurologic system, there are also diseases of the central nervous system classified as degenerative. Such diseases include supranuclear palsy (SNP), Alzheimer's, and Parkinson's. Alzheimer's is likely the most common cause of dementia first described in 1907. This disease may be depicted as presenile or senile dementia and progresses at a similar rate no matter age of onset. This disease has a genetic predisposition causing it to occur in younger age groups. Histological changes include diffuse plaques (containing amyloid), neurofibrillary plaques, and neuronal loss especially in the hippocampus and temporal regions. Medical management may reverse some of the symptoms but does not prevent disease progression. Parkinson's is a mainly sporadic degenerative disease with a gradual progressive course mainly affecting motor function more than memory. It was first described in 1817. This is a disease of the substantia nigra characterized by loss of melanin containing nerve cells and eosinophilic intracytoplasmic inclusions. Aside from emotional support and physical therapy, medical therapy is used to decrease tremors including anticholinergic drugs for tremors at onset, beta blockers for intention tremors, and levodopa for postural imbalance and akinesia. Deep brain stimulation is also used to treat symptoms later on as disease progresses. SNP starts in the same age range as Parkinson's (middle to later in life) that was first described in 1963 with disturbances in gait and balance secondary to rigidity of trunk muscles. Loss of neurons and gliosis is seen in the midbrain. Medical treatment is relatively unsuccessful. Multiple sclerosis is a demyelinating disease most often seen in young adults. The clinical manifestations are diverse and the progression can be chronic, acute, or remitting and relapsing. Medications and therapeutic plasma exchange have been used to treat this debilitating disease with limited efficacy. Clinical trials are ongoing looking at Mab therapies for treatment of these four neurologic degenerative diseases.

Alemtuzumab (Lemtrada) is a humanized Mab (IgG1k) targeting CD52 that depletes lymphocytes (B and T cell) as reported earlier and is FDA approved for treatment of acute relapsing and remitting multiple sclerosis. 292 Ocrelizumab (Ocrevus) is a humanized Mab (IgG1k) with specificity to CD20 (a B-cell membrane protein). In phase II trials, there were decreases in brain lesions on imaging, and decrease rate of disability decline in primary progressive multiple sclerosis. 293 Natalizumab (Tysabri) is a monoclonal IgG4k humanized antibody with specificity to cell adhesion molecule (CD62L) that is FDA approved for relapsing multiple sclerosis. 294, 295 The mabs to watch out for in the future and are in clinical trials include anifrolumab a human monoclonal antibody in phase I trials; elezanumab is a human Mab (IgG1l) with specificity to repulsive guidance molecule family member-A that is in phase II trials to be completed 2021; and finally inebilizumab (MEDI-551) is a humanized monoclonal antibody (IgG2k) with specificity to CD19 (a B-cell lymphocyte protein). This Mab mechanism of action is via ADCC and has completed phase I trials with good safety profile and response in decreasing lesions seen on contrast enhanced magnetic resonance imaging. Otilimabis (MOR103) is a human Mab (IgG1l) completing phase I studies with good safety profile that targets granulocyte-macrophage colonystimulating factor. Ublituximab is in phase II clinical studies to be completed in 2019, and phase III studies are scheduled to be completed in 2021. This Mab is a chimeric Mab (IgG1k) with specificity to CD20 MS2A1. 296e300 Additional Mab have serious adverse effects such as daclizumab a humanized monoclonal (IgG1k) with specificity to (CD25 {IL-2Ra}); or are ineffective as is opicinumab a human Mab IgG1 with specificity to Leucine-rich repeat and immunoglobulin domain containing neurite outgrowth inhibitor receptor interacting protein-1 which in a phase II trial was no more beneficial than placebo in treating optic neuritis in multiple sclerosis patients. 301, 302 Alzheimer's Disease Aducanumab is a human Mab IgG1 with specificity to b-amyloid (N-terminus 3e6) soluble oligomers and insoluble fibers. Phase III clinical trials are ongoing since 2015.

BAN-2401 is a humanized Mab IgG1 with specificity to b-amyloid fibrillary and soluble b amyloid and is in phase IIb clinical studies since 2013.

Gosuranemab (BIIB092, IPN-007) is a humanized Mab IgG4k with specificity to the tau protein and is in clinical trials to treat Alzheimer's disease scheduled to be completed in 2021. Gosuranemab is also in phase I studies to treat progressive suranuclear palsy and will be completed in 2020.

Crenezumab (RG7412, MABT5102A) is a humanized Mab IgG4 with specificity to 1e40 b-amyloid and is on phase III studies scheduled to be completed in 2021 and 2022.

Gantenerumab (R04909832, R1450) is a human Mab IgG1k with targets b-amyloid. This Mab on initial phase III studies was found to be ineffective. Ongoing phase II/III trials are currently in place at higher dosing in a clinical population of people with autosomal dominant form of Alzheimer's disease.

Solanezumab (LY2062430) is a humanized Mab IgG1 with specificity to beta amyloid. Initial phase III trials discontinued for lack of efficacy in preventing Alzheimer's disease. Ongoing phase III trials are now in place for secondary prevention of this disease and will be completed in 2021 and 2022.

Mab antibodies studied and were ineffective include bapineuzumab, gantenerumab (R04909832, R1450), and ponezumab (RN1219, PF-04,360,365).

Prasinezumab (PRX002, RG7935, RO7046015) is a humanized Mab IgG1k with specificity to a-synuclein. This Mab is in phase II clinical trials to treat Parkinson's and will be completed in 2021.

Allergic reactions develop because of immunologic stimulation of IgE antibodies followed by their interaction with allergens and mast cells. Effects can be local (dermatitis) or systemic (respiratory, cardiovascular, and gastrointestinal). Treatment is either avoidance of the allergens or supportive therapy in acute allergic reactions including pharmacologic treatment with type 1 and 2 histamine blockers, glucocorticosteroids, and if lifethreatening epinephrine. Passive antibody therapies are being studied and approved to curtail severe reactions.

Asthma affects 24 million individuals in the US, and up to 10% of asthma patients have severe disease that may be uncontrolled despite high doses of standard-of-care asthma medications requiring additional use of chronic oral corticosteroids. Benralizumab (Fensenra) is a humanized Mab (IgG1k) with specificity to CD125 (IL-5Ra). This Mab is approved to treat severe asthma of the eosinophilic subtype in ages 12 and older. Its mechanism of action is to decrease the number of eosinophils via ADCC. Basophils are also depleted. 303 

Dupilumab (Dupixent) is a human monoclonal gG4 antibody with specificity to interleukin-4 receptor subunit-alpha (IL-4Ra) that is approved to treat severe atopic dermatitis in adults. 304 

Coagulopathies are usually either autoimmune or genetic. In factor VIII deficiency, recombinant factor VIII is used to replace lack of this protein. However, patients may develop antibodies to factor VIII leading to high titers of inhibitors. Furthermore, patients without deficiency may also develop autoantibodies to factor VIII de novo leading to coagulopathies. Other factor combinations as well as recombinant active factors have been created to overcome these inhibitory antibodies. Mabs with bispecific binding are also being researched as another avenue for treatment.

ITP can lead to critical low platelet levels increasing risk for severe bleeding. ITP can occur in both adult and pediatric settings as it is considered an autoimmune disease. Typically, this is treated with steroids and IVIG. In addition, as mentioned earlier, RhD þ patients have benefitted from polyclonal medications directed against the D antigen. Recently, Mab to treat this disease have been developed and will be discussed next.

Thrombotic thrombocytopenic purpura (TTP) is a blood disorder that does not lead to bleeding but to development of diffuse thrombi in small blood vessels. More often, this disorder is secondary to an autoimmune inhibitory antibody to the disintegrin and metalloproteinase with thrombospondin type 1 motif member-13 (ADAMTS-13), known as acquired TTP. Inhibiting this zinc containing metalloprotease leads to lack of cleavage of large multimers of von Willebrand Factor (vWF). The large vWF multimers then more easily bind to platelets resulting in platelet clots in small blood vessels. More rarely, this disorder is secondary to an inherited deficiency of ADAMTS-13. This patient population with congenital deficiency is managed with transfusion of FFP to replace the deficient enzyme. Acquired TTP is typically treated with therapeutic plasma exchange (TPE). This treatment modality removes the inhibitory antibody and ultralarge vWF multimers. Similarly, TPE will replete the missing enzyme. Immunosuppressive agents may be added if only TPE is not effective. A Mab preventing interaction of vWF and platelets was recently approved for use in treating this disorder. 305, 306 Caplacizumab-yhdp (Cablivi) is a humanized single-variable-domain immunoglobulin (Nanobody) that inhibits the interaction between ultralarge vWF multimers and platelets and is directed against vWF. It induces a faster response to therapy with TPE and decreases relapse with continued use during TPE. This medication is then used post-TPE treatment until immunological evidence of disease is controlled to prevent relapse. 305, 307, 308 This medication was FDA approved for use in TTP in 2019.

Atypical hemolytic uremic syndrome (aHUS) is a disorder of the complement system due to uncontrolled activation. This disorder presents with thrombocytopenia, thrombi, and renal dysfunction. Historically, this illness was treated with TPE; however, end-stage renal failure occurred in 30% of patients and about 65% mortality in subsequent relapses with increasing incidence of renal failure. There are now two monoclonal antibodies approved for the treatment of aHUS. Refer to 

In sickle cell disease, one of the frequent complications is pain crises. This is usually treated with analgesics, oxygen, hydration, and transfusions (simple or exchange). Monoclonal antibodies are being developed to treat pain crises in sickle cell patients in both adult and pediatric populations. Crizanlizumab is a humanized Mab (IgG2k) with specificity to selectin P. One phase II trial was completed in 2016 and three additional phase II studies will be completed between 2021 and 27 to treat vasoocclusive pain crisis. This medication may be under FDA review as early as 2019. 309, 310 INFECTIONS Antimicrobials have historically been developed against a variety of viral, bacterial, fungal, and parasitic infections. These pharmaceuticals target differences from human cells of these particular organisms such as cell wall or membrane structure, genetic make-up, transcription/ translation of genetic material, or metabolic pathways.

Often organisms develop resistance to entire categories of these medications. Earlier in the chapter, passive polyclonal antibodies were discussed in the treatment of some of these infectious agents and we will now discuss research in monoclonal therapies to pathogenic microorganisms.

Enterocolitis from Clostridium difficile is a community or hospital acquired infection increasing morbidity and mortality in those that acquire it. Treatment is supportive or with fecal transplants or antibiotics. Bezlotoxumab (Zinplava) is a human Mab (IgG1) with specificity to Clostridium difficile's B toxin. It is used to treat pseudomembranous colitis and prevent C. difficile reinfection. 311, 312 Actoxumab, a monoclonal antibody against C. difficile toxin A, has shown not to be clinically significant.

Respiratory syncytial virus (RSV) infects almost all children by 2 years old and poses extra risk in preterm infants. Supportive therapy, RSV-IG or IVIG, and antiviral therapy have been used to mitigate the sequela of this infection with optimal response yet to be seen. No vaccines have yet to be developed for this infection. Recently, monoclonal antibodies have been FDA approved or are undergoing pre/clinical trials to treat this infectious process and include palivizumab, Nirsevimab (MEDI8897), TRL3d3 (3D3), and ALX-0171. 313, 314 Not beneficial or safe in use for RSV: motavizumab, Suptavumab (REGN2222, SAR438584).

Influenza is a worldwide respiratory infectious problem with cyclic epidemics yearly. Supportive therapy, yearly vaccinations, and antivirals are used to decrease the morbidity and mortality caused by this sometimes virulent pathogen. Both polyclonal and monoclonal therapies are being evaluated to better treat these infections. Mabs in pre/clinical trials include diridavumab (CR6262), firivumab, gedivumab (RG7745, RO6876802), lesofavumab (RG70026), and Navivumab (CT-P27).

Rabies is a devastating viral infection with swift mortality if not treated quickly after initial exposure. Vaccines usually react too slowly and have to be combined with polyclonal IVIG infusions. Monoclonal therapy was previously studied but usually the virus mutates quickly and the infection is not controlled. More recently, in clinical trials, cocktails of Mabs are being tried to more closely mimic the benefits of polyclonal therapies. These Mabs include foravirumab, rafivirumab (CR57), and Rmab.

HBV is one of if not the most common infections in the world. Even though antivirals are available and effective, only recently they have they been widely used in the infant population and not just "high"-risk individuals. Mabs to treat this infection that are being investigated include libivirumab. Mab that is not found to be effective is tuvirumab.

Ebola is a relatively rare but devastating hemorrhagic infection. Most care is supportive with various studies being performed to prevent/mitigate this disease. Vaccines are under development as well as passive polyclonal therapies. Mab therapies being developed or studied include porgaviximab (C2G4), cosfroviximab, and larcaviximab.

For these and other bacterial, fungal, and viral antiinfectious agents, information may be found in 

In solid organ transplants, cellular or humoral immunity can develop against the transplant leading to acute or chronic rejection. An additional complication with these and stem cell transplants is severe GVHD. In the past, these transplant complications were treated with high-dose glucocorticosteroids, immunosuppressive medication, chemotherapeutic agents, IVIG, or T-cell lymphocytic specific immunoglobulins. Recently, Mabs have been added to this armamentarium to better control these adverse reactions to transplantations. Basiliximab (Simulect) is a chimeric Mab (IgG1k) with specificity to CD25 IL-2a. The only FDAapproved indication for this medication is prophylaxis of acute rejection in renal transplant patients. There are multiple ongoing studies of this biological for other organ transplants including liver, lung, and heart as well as for inflammatory/immunologic diseases such as GVHD following stem cell transplantation, ulcerative colitis, and uveitis. 315e319 Belatacept (Nulojix) is a soluble fusion protein consisting of the modified extracellular domain of CTLA-4 fused to the Fc domain of a recombinant human Mab IgG1. This Mab selectively inhibits T-cell activation through costimulation blockade binding to both CD80 and CD86 while blocking CD28 via tighter binding than its parent antibody abatacept. Refer to 

Hypercholesterolemia is associated with increased risk for cardiovascular disease/atherosclerosis secondary to inherited or dietary etiologies. Diet and exercise are used to treat mild forms of these disorders. Medications such as nicotinic acid, fibrates, bile acid binding resins, and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors are used for more severe forms of these disorders. Phase III studies have been completed with monoclonal antibodies for patients' refractory to the previously mentioned forms of therapy.

Burosumab (KRN23, Crysvita) is a human Mab IgG1k with specificity to phosphaturic hormone fibroblast growth factor 23 (FGF 23). This hormone is a regulator of phosphate and vitamin D homeostasis. FGF23 inhibits the enzyme CYP27B1 and stimulates CYP24A1, thereby reducing circulating levels of 1,25dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D. This medication is FDA approved for the treatment of X-linked hypophosphatemic rickets. 320, 321 Osteoporosis Denosumab (Prolia) is an FDA-approved human Mab (IgG2) that is a receptor activator of nuclear factor kB ligand that inhibits development and activity of osteoclasts. As Prolia, this medication is used to prevent or treat osteoporosis in women. 322e324 This medication under the trade name Xgeva is also used to prevent skeletal-related events in adults with bone metastasis from breast, prostate cancers, and multiple myeloma. 325, 326 ENDOCRINE DISORDERS Diabetes may be classified as primary or secondary. In this chapter, we will be mainly interested in both insulin-dependent (Type I) and insulin-independent types (Type II). Type I diabetes mellitus is generally secondary to loss of b cells in the islets of Langerhans and subsequent loss of insulin production. Type II typically is secondary to decreased sensitivity to the effects of insulin. In type I, insulin is replaced exogenously depending on glucose levels. In type II, medications are given to stimulate islet cells to produce more insulin. Mabs are being developed to potentially mitigate the autoimmune process leading to Type I diabetes mellitus or the sequela of renal failure often seen with this disease. For type II, Mabs are being investigated to potentially decrease body mass index and thus decrease disease severity. Refer to 

Age-related macular degeneration (AMD) is the leading irreversible cause of visual loss affecting the elderly. Two forms include a dry form with deposits in the macula or a wet form involving abnormal growth of blood vessels. The wet form, even though less frequent, is associated with more severe visual acuity loss. Antiangiogenesic drugs or laser treatments are used to slow the progression or even partially reverse visual loss. Some trials have been completed while others are ongoing using Mab to treat the wet form of AMD. Brolucizumab was found as good as if not better than aflibercept in a phase III clinical trial. 327 Cryopyrin-associated periodic syndromes (including familial cold auto-inflammatory syndrome and Muckle-Wells syndrome); tumor necrosis factor receptor-associated periodic syndrome (TRAPS); hyperimmunoglobulin D Syndrome (HIDS)/mevalonate kinase deficiency and familial Mediterranean fever (FMF) may also respond to canakinumab. 328 

Passive antibody therapy continues to be useful clinically whether polyclonal or monoclonal therapy is implemented. Increased utilization of the classic polyclonal antibody preparations continue especially in the realm of infections. In the past 3 years, monoclonal therapy has evolved and revolutionized treatment in many areas. As targets are identified to modify disease pathology no matter its genre we continue to get a better handle on morbidity and mortality. We are learning that not only is the target important put the portion of the target mediating the effect we intend to modify is also important. Importantly, modification of antibodies to be more compatible with the immune system while decreasing rapidity of clearance also allows for more consistent therapy. There are also many targets yet to be discovered or only now being developed as in the canonical wingless/integrated (WNT) signaling. This receptor family is important in a multitude of diseases not limited to: hereditary colorectal cancer, various types of sporadic cancers, intellectual disability syndrome, Alzheimer's disease, bipolar disorder, bone diseases, and vascular diseases. One monoclonal antibody rosmantuzumab (OMP-131R10), a humanized Mab (IgG1k), is in phase I trials to treat colorectal cancer. 329, 330 Other disease processes have yet to find their optimal therapy (Alzheimer's) or are advancing to fuller therapeutic benefit. The future is wide open for this newer class of pharmaceuticals as they continue to develop to full fruition.

Thymoglobulin; (Antithymocyte Globulin [rabbit]) Prescribing Information

Antithymocyte globulin (rabbit): a review of the use of Thymoglobulin in the prevention and treatment of acute renal allograft rejection

Atgam Prescribing Information

The clinical value of antilymphocyte antibodies

The clinical usefulness of antilymphocyte antibodies

Antithymocyte globulin, pretransplant blood transfusion, and tissue typing in cadaver kidney transplantation

Antithymocyte globulin as the primary treatment for renal allograft rejection

Use of ATG for reversal of acute allograft rejection

Use of ATG in treatment of steroid-resistant rejection

Reversal of acute cadaveric renal allograft rejection with added ATG treatment

Results of the doubleblind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation

A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients

Mode of action of antilymphocyte serum

Site of action of antilymphocyte globulin

Nature and mode of action of antilymphocytic antiserum

The immunosuppressive properties of antilymphocyte serum preparations: a current review

Immunosuppressive antilymphocyte serum: different subpopulations of T lymphocytes are influenced at different doses of antilymphocyte serum

Mechanism and significance of rosette inhibition by antilymphocyte serum

Antithymocyte antiserum effects in man

Antithymocyte globulin reacts with many normal human cell types

GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute leukaemia in remission: final results of quality of life and longterm outcome analysis of a phase 3 randomised study. The Lancet

Aplastic anemia: biology and treatment

Antithymocyte globulin treatment in patients with aplastic anemia

Controlled clinical trial of prophylactic human-leukocyte interferon in renal transplantation: effects on cytomegalovirus and herpes simplex virus infections

Epstein-Barr virus infection in renal transplant recipients: effects of antithymocyte globulin and interferon

Clinical evaluation of equine antithymocyte globulin in recipients of renal allografts: analysis of survival, renal function, rejection, histocompatibility, and complications

HyperTET S/D (Tetanus Immune Globulin [human]) Solvent/detergent Treated Prescribing Information

General recommendations on immunization: recommendations of the advisory committee on immunization practices (ACIP). MMWR Recomm Rep

Prevention of pertussis, tetanus, and diphtheria among pregnant and postpartum women and their infants recommendations of the Advisory Committee on Immunization Practices (ACIP)

Public Health Foundation

CytoGam (Cytomegalovirus Immune Globulin Intravenous [human][CMV-IG]) Liquid Formulation Solvent Detergent Treated Prescribing Information

A pilot trial of a novel cytomegalovirus immune globulin in renal transplant recipients

Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal-transplant recipients

Prevention of cytomegalovirus-associated diseases with immunoglobulin

Final analysis of primary cytomegalovirus disease prevention in renal transplant recipients with a cytomegalovirus-immune globulin: comparison of the randomized and openlabel trials

Cytomegalovirus immune globulin for the prevention of primary CMV disease in renal transplant patients: analysis of usage under treatment IND status

s Principles and Practice of Infectious Diseases

Studies evaluating high-dose acyclovir, intravenous immune globulin, and cytomegalovirus hyperimmunoglobulin for prophylaxis against cytomegalovirus in kidney transplant recipients

Cytomegalovirus immunoglobulins in the prevention and treatment of cytomegalovirus disease

Cytomegalovirus prophylaxis in solid organ transplant recipients

Prevention of cytomegalovirus infection after marrow transplantation

Cytomegalovirus infections after allogeneic bone marrow transplantation

Prevention and treatment of cytomegalovirus disease in thoracic organ transplant patients: evidence for a beneficial effect of hyperimmune globulin

Virologic and pathogenetic aspects of cytomegalovirus infection

Efficacy of immune globulin in preventing complications of bone marrow transplantation: a meta-analysis

Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells

Cytomegalovirus prophylaxis and treatment following bone marrow transplantation

Use of cytomegalovirus (CMV) hyperimmune globulin for prevention of CMV disease in CMV-seropositive lung transplant recipients

A further analysis of the use of cytomegalovirus immune globulin in orthotopic liver transplant patients at risk for primary infection

Prospective randomized trial of efficacy of ganciclovir versus that of anti-cytomegalovirus (CMV) immunoglobulin to prevent CMV-seropositive heart transplant recipients treated with OKT3

Latrodectus Mactans) (Black Widow Spider Antivenin) Equine Origin Prescribing Information

Clinical presentation and treatment of black widow spider envenomation: a review of 163 cases

Micrurus fulvius) (Equine Origin) (North American Coral Snake Antivenin) Prescribing Information

The United States Pharmacopeia, 25th Rev, and the National Formulary

Crotalidae Polyvalent Immune Fab [ovine]) Prescribing Information

Bites by coral snakes: report of 11 representative cases

Identification and distribution of North American venomous snakes

New world coral snakes (Elapidae): a taxonomic and biologic summary

Treatment of snakebite in the USA

Immediate and delayed allergic reactions to Crotalidae polyvalent immune Fab (ovine) antivenom

Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop

clinical decision making support for treatment

Metaanalysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment?

Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection

First Ebola treatment is approved by WHO

Treatment of Ebola hemorrhagic fever with blood transfusions from convalescent patients. International Scientific and Technical Committee

Should blood be an essential medicine?

External financial aid to blood transfusion services in sub-Saharan Africa: a need for reflection

Ebola: a call for blood transfusion strategy in sub-Saharan Africa

Digoxin Immune Fab [ovine]) Prescribing Information

Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies

Treatment of lifethreatening digitalis intoxication with digoxin-specific Fab antibody fragments

Use of digoxin-specific Fab fragments in the treatment of digitalis intoxication

Cardiac glycoside-specific antibodies in the treatment of digitalis intoxication

Treatment of 63 severely digitalis-toxic patients with digoxin-specific antibody fragments

Reversal of digitalis effects by specific antibodies

Digoxin specific antibody (Fab) fragments in 34 cases of severe digitalis intoxication

Digifab (Digoxin Immune Fab [ovine]) Prescribing Information

Use of antibodies in the study of the mechanism of action of digitalis

Biologic activity of digoxin-specific antisera

Antibodies as specific antagonists of toxins, drugs, and hormones

Effects of digoxinspecific antibodies on accumulation and binding of digoxin by human erythrocytes

Immunotherapy in the poisoned patient

Digoxin-specific antibody fragments for the treatment of digoxin intoxication

Reversal of digoxin toxicity with specific antibodies

Effects of sheep digoxin-specific antibodies and their Fab fragments on digoxin pharmacokinetics in dogs

The isolation of digoxin-specific antibody and its use in reversing the effects of digoxin

Enzymatic digestion of rabbit gamma globulin and antibody and chromatography of digestion products

Digoxin-specific Fab fragments as single first-line therapy in digitalis poisoning

Digoxin toxicity: pediatric survival after asystolic arrest

Digoxin-specific antibody fragments: how much and when?

Treatment of chronically digoxin-poisoned patients with a newer digoxin immune fab-a retrospective study

Digoxin specific antibody fragments (Digibind) in digoxin toxicity

Fab antibody fragments: some applications in clinical toxicology

Treatment of severe digoxin toxicity with digoxin-specific antibodies: a case report

Use of amiodarone and digoxin specific Fab antibodies in digoxin overdosage

General recommendations on immunization: recommendations of the advisory committee on immunization practices (ACIP). MMWR Recomm Rep

Report of the Committee on Infectious Diseases

Hepatitis B Immune Globulin [human] Solvent/detergent Treated) Prescribing Information

Nabi-HB (Hepatitis B Immune Globulin [human] Solvent/detergent Treated and Filtered) Prescribing Information

A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Part I: immunization of infants, children, and adolescents

A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Part II: immunization in adults

HepaGam B (Hepatitis B Immune Globulin Intravenous [human]) Prescribing Information

Report of the Committee on Infectious Diseases

Recommended immunization schedules for persons 0 through 18 yearseUnited States

Protection against viral hepatitis: recommendations of the immunization practices advisory committee (ACIP)

Sexually transmitted diseases treatment guidelines

Updated US Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis

Management of hepatitis B in liver transplant recipients

Prophylaxis against recurrence of hepatitis B virus after liver transplantation: a retrospective analysis spanning 20 years

Hepatitis B in liver transplant recipients

Intramuscular hepatitis B immunoglobulin (HBIG) and nucleosides for prevention of recurrent hepatitis B following liver transplantation: comparison with other HBIG regimens

Lamivudine plus low-dose hepatitis B immunoglobulin to prevent recurrent hepatitis B following liver transplantation. Gastroenterology

Hepatitis B prophylaxis post-liver transplant without maintenance hepatitis B immunoglobulin therapy

Prevention of hepatitis B virus recurrence after liver transplantation

Prevention of hepatitis B recurrence after liver transplantation using lamivudine or lamivudine combined with hepatitis B immunoglobulin prophylaxis

Varizig Varicella Zoster Immune Globulin (Human) Lyophilized Powder for Solution for Injection for Intramuscular Administration Only Prescribing Information

National Center for Immunization and Respiratory Diseases. General recommendations on immunization -recommendations of the advisory committee on immunization practices (ACIP)

Report of the Committee on Infectious Diseases

FDA approval of an extended period for administering Vari-ZIG for postexposure prophylaxis of varicella

Myobloc (rimabotulinumtoxinB) Injection Prescribing Information

Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-responsive cervical dystonia

Botulism type B: epidemiologic aspects of an extensive outbreak

Unlabeled uses of botulinum toxins: a review, part 1

Botox (onabotulinumtoxinA) for Injection Prescribing Information

Pharmacotherapy with botulinum toxin: harnessing nature's most potent neurotoxin

Botulinum toxin as a therapeutic agent

Botulinum toxin A (BoNT-A) for spasticity in adults. What is the evidence?

Botulinum toxin A compared with stretching casts in the treatment of spastic equinus: a randomised prospective trial

Botulinum toxin B: a review of its therapeutic potential in the management of cervical dystonia

Botulinum toxin type B: a double-blind, placebo-controlled, safety and efficacy study in cervical dystonia

Botulinum toxin for cervical dystonia

BabyBIG (Botulism Immune Globulin Intravenous [human]) Prescribing Information

Creation and development of the public service orphan drug Human Botulism Immune Globulin

Infant Botulism Treatment and Prevention Program. Division of Communicable Disease Control, California Department of Health Services. From IBTPP website

Infant botulism: a 30-year experience spanning the introduction of botulism immune globulin intravenous in the intensive care unit at Childrens Hospital Los Angeles

Feigin: Feigin and Cherry's Textbook of Pediatric Infectious Diseases

Human botulism immune globulin for the treatment of infant botulism

HyperRAB S/D (Rabies Immune Globulin [human] Solvent/detergent Treated) Prescribing Information

Imogam Rabies-HT (Rabies Immune Globulin [human] USP, Heat Treated) Prescribing Information

Recommendations of the advisory committee on immunization practices

Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies. Recommendations of the Advisory Committee on Immunization Practices

WinRho SDF (Rho [D] Immune Globulin Intravenous [human]) Prescribing Information

Ultra-filtered PLUS Prescribing Information

The United States pharmacopeia. 23rd Rev, and the National Formulary

Rhophylac (Rho [D] Immune Globulin Intravenous [human]) Prescribing Information. IL: Kankakee

Universal RDH genotyping in fetuses

Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect

Treatment of childhood idiopathic thrombocytopenic purpura with Rhesus antibodies (anti-D)

A multicenter study of the treatment of childhood chronic idiopathic thrombocytopenic purpura with anti-D

Intravenous anti-D treatment of immune thrombocytopenic 20. Ballow M. Mechanisms of action of intravenous immunoglobulin therapy and potential use in autoimmune connective tissue diseases

Mechanisms of action of intravenous immunoglobulin therapy and potential use in autoimmune connective tissue diseases

Immunosuppressive agents, g-globulin, immunomodulation, immunization, and aphresis

Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura

Therapy of chronic idiopathic thrombocytopenic purpura in adults

A followup study of 49 adult patients with idiopathic thrombocytopenic purpura treated with high-dose immunoglobulins and anti-D immunoglobulins

Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura

HIV-related severe thrombocytopenia in intravenous drug-users: prevalence, response to therapy in a medium-term follow-up, and pathogenetic evaluation

Human immunodeficiency virus-associated thrombocytopenia

FDA Application: Search Orphan Drug Designations and Approvals

Anti-RH immunoglobulin therapy for human immunodeficiency virus-related immune thrombocytopenic purpura

Intramuscular versus intravenous anti-D for preventing Rhesus alloimmunization during pregnancy

Nanofiltered (Immune Globulin Intravenous [human] Lyophilized for Solution) Prescribing Information

Immune Globulin Intravenous [human] IgA Less than or Equal to 2.2 mcg/mL in a 5% Solution) Prescribing Information

Prescribing Information

Immune Globulin Intravenous [human] 5% Liquid) Prescribing Information

Grifols Therapeutics Inc. Gamunex-C (Immune Globulin Intravenous [human] 10% Caprylate/chromatography Purified) Prescribing Information

Immune Globulin Intravenous [human] IgA Less than 1 mcg/mL in a 5% Solution) Prescribing Information

Privigen (Immune Globulin Intravenous [human] 10% Liquid) Prescribing Information

Report of the Committee on Infectious Diseases

Intravenous immunoglobulin: prevention and treatment of disease

Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial

CSL Behring. Hizentra (Immune Globulin Subcutaneous

Gammaplex (Immune Globulin Intravenous [human] 5% Liquid for Intravenous Use) Prescribing Information

Bivigam (Immune Globulin Intravenous [human] 10% Liquid) Prescribing Information

Flebogamma 10% DIF (Immune Globulin Intravenous [human] Solution for Intravenous Administration) Prescribing Information

Immune Globulin Intravenous [human] 10% Liquid) Prescribing Information

Immune Globulin [human] 10% with Recombinant Human Hyaluronidase Solution for Subcutaneous Administration) Prescribing Information

Cuvitru (Immune Globulin Subcutaneous [human] 20% Solution) Prescribing Information

Immune Globulin Intravenous [human] 10% Caprylate/chromatography Purified) Prescribing Information

Prevention of hepatitis A through active or passive immunization: recommendations of the advisory committee on immunization practices (ACIP)

Update: prevention of hepatitis A after exposure to hepatitis A virus and in international travelers

Updated dosing instructions for immune globulin (human) GamaSTAN S/D for hepatitis a virus prophylaxis

GA: US Department of Health and Human Services

Prevention of measles, rubella, congenital rubella syndrome, and mumps

Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies-a prospective, multi-national study

Health-related quality of life and treatment satisfaction in north american patients with primary immunedeficiency diseases receiving subcutaneous IgG self-infusions at home

Immunoglobulin replacement treatment by rapid subcutaneous infusion

Flebogamma 5% DIF (Immune Globulin Intravenous [human] Solution for Intravenous Administration) Prescribing Information

Efficacy of intravenous gamma globulin in autoimmune-mediated pediatric blood dyscrasias

Use of intravenous gamma globulin in children and adolescents with idiopathic thrombocytopenic purpura and other immune thrombocytopenias

Clinical uses of intravenous immunoglobulins

Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia

Clinical uses of intravenous immune globulin

The treatment of Kawasaki syndrome with intravenous gamma globulin

Highdose gammaglobulin therapy for Kawasaki disease

Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the committee on rheumatic fever, endocarditis and Kawasaki disease, council on cardiovascular disease in the young

Monoclonal antibodies: a review

HIGHLIGHTS OF PRESCRIBING INFORMATION: RIT-UXAN HYCELA (rituximab and hyaluronidase human) injection, for subcutaneous use Initial

Rituximab in Bcell hematologic malignancies: a review of 20 Years of clinical experience

An IgG1-like bispecific antibody targeting CD52 and CD20 for the treatment of B-cell malignancies

Mini-review: ofatumumab. mAbs

Therapeutic CD94/NKG2A blockade improves natural killer cell dysfunction in chronic lymphocytic leukemia

Randomized phase 2 study of otlertuzumab and bendamustine versus bendamustine in patients with relapsed chronic lymphocytic leukaemia

Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody

gov Clinical trial; Urelumab (CD137 mAb) with rituximab for relapsed, refractory or high-risk untreated chronic lymphocytic leukemia (CLL) patients

Ulocuplumab (BMS-936564/MDX1338): a fully human anti-CXCR4 antibody induces cell death in chronic lymphocytic leukemia mediated through a reactive oxygen speciesdependent pathway

Tolerability and Preliminary Efficacy of an Anti-CXCR4 Antibody in Subjects With Acute Myelogenous Leukemia and Selected B-cell Cancers

A phase I/II dose escalation study of apolizumab (Hu1D10) using a stepped-up dosing schedule in patients with chronic lymphocytic leukemia and acute leukemia

A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors

Dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide as salvage therapy for patients with diffuse large B-cell lymphoma relapsing after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone: a randomized, double-blind, placebo-controlled phase 2b trial

A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia

A CD123-targeting antibody-drug conjugate, IMGN632, designed to eradicate AML while sparing normal bone marrow cells

T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bispecific BiTE antibody construct. Leukemia

CD123 target validation and preclinical evaluation of ADCC activity of anti-CD123 antibody CSL362 in combination with NKs from AML patients in remission

NIH: National Library of Medicine at Clinicaltrials.gov Clinical trial; Study of Biomarker-Based Treatment of Acute Myeloid Leukemia

NIH: National Library of Medicine at Clinicaltrials.gov Clinical trial; Ficlatuzumab With High Dose Cytarabine in Relapsed and Refractory AML

The return of gemtuzumab ozogamicin: a humanized anti-CD33 monoclonal antibodyedrug conjugate for the treatment of newly diagnosed acute myeloid leukemia

Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, Lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia

Randomized, phase IIb study of low-dose cytarabine and lintuzumab versus low-dose cytarabine and placebo in older adults with untreated acute myeloid leukemia. Haematologica

Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors

Siltuximab (CNTO 328) with lenalidomide, bortezomib and dexamethasone in newly-diagnosed, previously untreated multiple myeloma: an open-label phase I trial

Approval Package for: APPLICATION NUMBER: 125496Orig1s000 Trade Name: Sylvant, Generic Name: siltuximab, Sponsor: Janssen Biotech

Potential for bispecific T-cell engagers: role of blinatumomab in acute lymphoblastic leukemia. Drug Des Dev Ther

Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia

blinatumomab) for injection, for intravenous use

Brentuximab vedotin: a review in CD30-positive Hodgkin lymphoma

ADCT-301, a pyrrolobenzodiazepine (PBD) dimerecontaining antibodyedrug conjugate (ADC) Targeting CD25-expressing hematological malignancies. Mol Cancer Ther

Study of ADCT-301 in Patients With Relapsed or Refractory Hodgkin and Non-Hodgkin Lymphoma

Phase I/II study of an anti-CD30 monoclonal antibody

Hodgkin's Lymphoma and anaplastic large-cell lymphoma

Phase IA/II, multicentre, open-label study of the CD40 antagonistic monoclonal antibody lucatumumab in adult patients with advanced non-Hodgkin or Hodgkin lymphoma

Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma

Atezolizumab and Nab-paclitaxel in advanced triple-negative breast cancer

Atezolizumab Plus nab-Paclitaxel in the treatment of metastatic triplenegative breast cancer with 2-year survival follow-up a phase 1b clinical trial

FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study

AVAS-TIN (bevacizumab) injection, for intravenous use

Atezolizumab: a PD-L1eblocking antibody for bladder cancer

Atezolizumab (MPDL3280A) monotherapy for patients with metastatic urothelial cancer long-term outcomes from a phase 1 study

Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057)

Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial

Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial

Bevacizumab and paclitaxelecarboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial

Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial

BAVENCIO (avelumab) injection, for intravenous use Initial U

NIH: National Library of Medicine at Clinicaltrials.gov for 175 Studies found for: Avelumab; Also searched for MSB0010718C and Bavencio. See search details available at

Dinutuximab: an anti-GD2 monoclonal antibody for high-risk neuroblastoma

Dinutuximab: first global approval. Drugs

The role of bevacizumab in the treatment of glioblastoma

gov Clinical trial; Anti-LAG-3 Alone & in Combination w/Nivolumab Treating Patients w/Recurrent GBM (Anti-CD137 Arm Closed 10/16/18) Available at

Phase I trial and pharmacokinetic study of tanibirumab, a fully human monoclonal antibody to vascular endothelial growth factor receptor 2, in patients with refractory solid tumors. Investig New Drugs

NIH: National Library of Medicine at Clinicaltrials.gov Clinical trial; Trial to Evaluate the Safety of TTAC-0001(Tanibirumab) in Recurrent Glioblastoma

NIH: National Library of Medicine at Clinicaltrials.gov Clinical trial; TTAC-0001 Phase II Trial With Recurrent Glioblastoma Progressed on Bevacizumab

Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM anti-CD3) as a targeted cancer immunotherapy

Novel monoclonal antibodies for cancer treatment: the trifunctional antibody catumaxomab (Removab)

Immunological changes in the ascites of cancer patients after intraperitoneal administration of the bispecific antibody catumaxomab (anti-EpCAM Â anti-CD3)

HIGHLIGHTS OF PRESCRIBING INFORMATION: LIB-TAYO (cemiplimab-rwlc) injection, for intravenous use Initial U.S. Approval: 09/2018 Last Revised 9

PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma

Efficacy of medical therapies for fistulizing Crohn's disease: systematic review and meta-analysis

Systematic review and network meta-analysis of treatment for moderate-to-severe ulcerative colitis

HUMIRA (adalimumab) injection, for subcutaneous use

Human antietumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial

Reinduction with certolizumab pegol in patients with Crohn's disease experiencing disease exacerbation: 7-year Data from the PRECiSE 4 study

Intravenous CDP870, a PEGylated Fab' fragment of a humanized antitumour necrosis factor antibody, in patients with moderate-to severe Crohn's disease: an exploratory study. Aliment Pharmacol Ther

Long-term safety and efficacy of certolizumab pegol in the treatment of Crohn's disease: 7-year results from the PRECiSE 3 study

The safety of vedolizumab for ulcerative colitis and Crohn's disease. Gut

A review of the clinical pharmacokinetics, pharmacodynamics, and immunogenicity of vedolizumab

Long-term outcomes of patients with Crohn's disease who received infliximab or adalimumab as the first-line biologics

Natalizumab for induction of remission in Crohn's disease (Review)

HIGHLIGHTS OF PRESCRIBING INFORMATION: TYSABRI (natalizumab) injection, for intravenous use Initial

Phase 3 studies comparing brodalumab with ustekinumab in psoriasis

SILIQ (brodalumab) injection, for subcutaneous use

Abatacept: a review in rheumatoid arthritis

Abatacept in the treatment of polyarticular JIA: development, clinical utility, and place in therapy. Drug Des Dev Ther

ORENCIA (abatacept) for injection for intravenous use injection, for subcutaneous use

Certolizumab pegol (CDP870) for rheumatoid arthritis in adults (Review)

Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebocontrolled, phase 3 trial

Belimumab Treatment for Adults with Systemic Lupus Erythematosus: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines. Ottawa: CADTH

Efficacy of belimumab on renal outcomes in patients with systemic lupus erythematosus: a systematic review

How abciximab might be clinically useful

Alirocumab dosing patterns during 40 months of open-label treatment in patients with heterozygous familial hypercholesterolemia

Efficacy and safety of alirocumab versus ezetimibe over 2 years (from ODYSSEY COMBO II)

Evolocumab and clinical outcomes in patients with cardiovascular disease

REPA-THA (evolocumab) injection, for subcutaneous use

Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled Phase 2 study

Cardiovascular event reduction with PCSK9 inhibition among 1578 patients with familial hypercholesterolemia: results from the SPIRE randomized trials of bococizumab

Alemtuzumab CARE-MS II 5-year follow-up: efficacy and safety findings

Ocrelizumab versus placebo in primary progressive multiple sclerosis

The effect of disease modifying therapies on CD62L expression in multiple sclerosis

TYSABRI (natalizumab) injection, for intravenous use

Suppression of T cell activation and collagen accumulation by an anti-FNAR1 mAb, Anifrolumab, in adult patients with systemic sclerosis

gov Clinical trial; A study to assess the safety and efficacy of elezanumab when added to standard of care in relapsing forms of multiple sclerosis

Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study

Randomized phase 1b trial of MOR103, a human antibody to GM-CSF, in multiple sclerosis

NIH: National Library of Medicine at Clinicaltrialsgov Clinical trial; A Phase 3, Randomized, Multi-center

UTX) as Compared to Teriflunomide in Subjects With Relapsing Multiple Sclerosis (RMS) (ULTIMATE 1)

Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MSSMART): a multi-arm phase IIb randomised, double-blind, placebo controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis

Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial

Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting b2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial

DUPIXENT (dupilumab) injection, for subcutaneous use Initial U

Caplacizumab: first global approval

Caplacizumab reduces the frequency of major thromboembolic events, exacerbations and death in patients with acquired thrombotic thrombocytopenic purpura

Caplacizumab for acquired thrombotic thrombocytopenic purpura

Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura

Crizanlizumab for the prevention of pain crises in sickle cell disease

NIH: National Library of Medicine at Clinicaltrials.gov Clinical trial; Study of Dose Confirmation and Safety of Crizanlizumab in Pediatric Sickle Cell Disease Patients

Bezlotoxumab: an emerging monoclonal antibody therapy for prevention of recurrent Clostridium difficile infection

Past, present and future approaches to the prevention and treatment of respiratory syncytial virus infection in children

Respiratory syncytial virus: targeting the G protein provides a new approach for an old problem

NIH: National Library of Medicine at Clinicaltrials.gov Clinical trial; 155 Studies found for: basiliximab

Efficacy and safety of basiliximab versus daclizumab in kidney transplantation: a meta-analysis

Review article: use of induction therapy in liver transplantation. Transplant Rev

Low-dose basiliximab induction therapy in heart transplantation

Comparison of basiliximab vs antithymocyte globulin for induction in pediatric heart transplant recipients: an analysis of the International Society for Heart and Lung Transplantation database

Burosumab: a new drug to treat hypophosphatemic rickets

A randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy of burosumab, an anti-FGF23 antibody, in adults with X-linked hypophosphatemia: week 24 primary analysis

Denosumab for prevention of fractures in postmenopausal women with osteoporosis

Denosumab for the treatment of osteoporosis

Denosumab: a review in postmenopausal osteoporosis

A comprehensive review of denosumab for bone metastasis in patients with solid tumors

Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, doubleblind, double-dummy, randomised, controlled, phase 3 study

Brolucizumab versus Aflibercept in participants with neovascular age-related macular degeneration: a randomized trial

ILA-RIS (canakinumab) injection, for subcutaneous use

Multi-layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/b-catenin signaling activation (Review)

Molecular genetics and targeted therapy of WNT-related human diseases (Review)

Guidance for Industry. Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jacob Disease (CJD) and Variant Creutzfeldt-Jacob Disease (vCJD) by Blood and Blood Products

Diphtheria, tetanus, and pertussis: recommendations for vaccine use and other preventive measures

Update on adult immunization: recommendations of the immunization practices advisory committee (ACIP)

Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine recommendations of the Advisory Committee on Immunization Practices (ACIP) and recommendation of ACIP, supported by the Healthcare Infection Control Practices Advisory Committee (HICPAC), for use of Tdap among health-care personnel

Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines recommendations of the Advisory Committee on Immunization Practices (ACIP)

Cytomegalovirus immune globulin prophylaxis in liver transplantation: a randomized, double-blind, placebo-controlled trial

Cytomegalovirus immune globulin and seronegative blood products to prevent primary cytomegalovirus infection after marrow transplantation

The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis

Guidance for Industry Influenza: Developing Drugs for Treatment And/or Prophylaxis. Silver Spring, MD: US Food and Drug Administration

Influenza hemagglutination-inhibition antibody titer as a correlate of vaccine-induced protection

for the Working Group on Civilian Biodefense. Botulinum toxin as a biologic weapon: medical and public health management