- Email: [email protected]
An Overview of Monoclonal Antibodies
Seminars in Oncology Nursing 35 (2019) 150927
Contents lists available at ScienceDirect
Seminars in Oncology Nursing journal homepage: https://www.journals.elsevier.com/seminars-in-oncology-nursing
An Overview of Monoclonal Antibodies Virginia Bayer, BSN, RN, OCNÒ ,* Department of Gynecology Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston TX
A R T I C L E
I N F O
Article History: Available online xxx Keywords: monoclonal antibodies (mAb) cancer murine chimeric immunotherapy
A B S T R A C T
Objective: To provide a brief overview of the development of monoclonal antibodies in immunotherapy, including a review of the mechanism of action and types, and indications for use. Data Source: Peer-reviewed journal articles, book chapters, internet. Conclusion: Monoclonal antibodies offer alternative treatment to cancer patients who have failed or progressed on standard chemotherapy. Clinical research continues to explore new antigens to target in hopes of discovering the “magic bullet” to eliminate cancer altogether. Implications for Nursing Practice: Collaboration with infection control should be considered for nurses administering monoclonal antibodies to ensure their safe handling. These agents should be verified before administration with the two-RN sign-off system. Nurses play a vital role in providing adequate patient education to ensure patient safety. © 2019 Elsevier Inc. All rights reserved.
History Monoclonal antibodies (mAbs) are defined as “laboratory-produced molecules engineered to serve as substitute antibodies that can restore, enhance, or mimic the immune system's attack on cancer cells” by binding to antigens found on the surface of cancer cells.1 Experiments to create this type of treatment have existed for more than a century.2 In the 18th century, it was discovered by Dr Edward Jenner that “fluid obtained from a smallpox pustule when injected into a recipient provided immunity from acquiring the disease.”3 This was part of the beginning stages of antibody development. In the 1930s and 1940s, several scientists’ work contributed to the concept of mAbs, including the isolation of agglutin from lymph nodes by McMaster and Hudack and the identification that lymphocytes are the source of antibody production.3 The earliest antibodies were traditionally created by “immunizing experimental animals with an antigen with subsequent purification of the serum to isolate the antibody fraction.”3 The first description of laboratory created mAbs was published in 1970, describing the technique of how a single plasma cell clone was isolated, which generated a homogenous antibody, proliferated by repeated passage of spleen cells into irradiated syngeneic mice. However, the first monoclonal antibody for human use was not generated until 1975, and the first monoclonal antibody was not fully licensed until 1986.4 Milstein and Kohler won the Nobel Prize in Physiology or Medicine in 1984,
* Address correspondence to: Virginia Bayer, BSN, RN, OCNÒ , Department of Gynecology Oncology & Reproductive Medicine, MD Anderson Cancer Center, Unit 1362, P. O. Box 301439, Houston, TX 77230-1439. E-mail address: [email protected] https://doi.org/10.1016/j.soncn.2019.08.006 0749-2081/© 2019 Elsevier Inc. All rights reserved.
being the first to be able to reproduce large amounts of mAbs in vivo.5 This was the birth of the “hybridoma’’ and the practice of producing mAbs was changed forever. The initial mAbs were generated utilizing murine (from mice) protein and were not well tolerated for long periods of time by humans. Therefore, the production mechanisms were forced to be reevaluated and eventually changed by the development of technology, allowing for fully humanized antibodies. The first monoclonal antibody to be approved by the US Food and Drug Administration was muromonab-CD3, which was used as an anti-rejection medication.3 The first monoclonal antibody that was found successful in the treatment of solid tumors was trastuzumab. This mAb was initiated by the humanized human epidermal growth factor receptor 2 (HER2).5 The laborious science that brought about trastuzumab also led to the beginning of drug discovery and treatment in cancer targeting a patient’s unique biomarkers. Pathophysiology The production and release of antibodies by plasma cells is part of the body’s normal immune response to a foreign substance or toxin. Scientists developed a method to engineer antibodies as a method of targeting cancer cells. Monoclonal antibodies, also known as mAbs, are substances developed in a laboratory that seek out and bind to specifically selected proteins wherever they may be in the body. The mAbs are structured by the binding of two heavy and two light polypeptide chains by a disulfide bond. The resultant “Y” formation includes the variable or “Fab” region, which varies according to the antigen being bound to it, and the “Fc” or constant region of the antibody, which is responsible for linking the antibody with cells
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involved in the immune response.6 Depending upon which antigen is bound to the antibody and the Fc region, an antibody-dependent cell cytotoxicity or complement-system cytotoxicity can be generated. This can result in the blocking of cell membrane receptors and inhibiting intracellular signals.7 Classification and Types of mAbs There are four classifications of mAbs: murine, chimeric, humanized, and human (see Table 1).6,7 The structure of mAbs is depicted in Figure 1.8 Murine The first mAb to be discovered and reproduced was the murine monoclonal antibody. This type of mAb arises from harvesting B lymphocytes from the spleen of a mice and then fused with an immortal myeloma cell line lacking the hypoxanthine-guanine-phosphoribosyltransferase (HPTR) gene.4 All of these mAbs are identified with a name that ends in -omab (ie, muromonab-CD3, blinatumomab, capromab). Allergic reactions are common when used in humans and often result in the induction of anti-drug antibodies. Murine mAbs also have a short half-life when used in humans because of a relatively weak binding to the human FcRn.6 For oncology, these mAbs may not be the most beneficial as they are “relatively poor recruiters of effector function, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity,” essential functions needed for tumor destruction.6 Chimeric Chimeric mAbs utilize the murine antigen-specific variable region, but the remaining heavy and light chains are human.7 This was accomplished using genetic engineering techniques, which resulted in mAbs that are approximately 65% human and 35% murine.6 The chimeric mAbs are identified with names ending in -ximab (ie, rituximab, infliximab, cetuximab). Compared with their murine counterparts, these mAbs “exhibit an extended half-life in man and show reduced immunogenicity, but nevertheless, the propensity of chimeric mAbs to induce anti-drug antibodies is still considerable.”6
These mAbs are identified with names ending in -zumab (ie, trastuzumab, alemtuzumab, bevacizumab). Human With the development of new technology, fully human mAbs were able to be created. These are created utilizing animals carrying human Ig genes. These transgenes include parts of the variable regions, which enable the recombination of the human antibodies.7 The animal’s own endogenous Ig genes have been inactivated, enabling the generation of fully human mAbs. These mAbs are less antigenic and better tolerated compared with the other classes of mAbs. Additionally, they appear to remain present in the human body’s circulation compared with the other classes.6 These mAbs are identified with names ending in -umab (ie, ofatumumab, daratumumab, denosumab). There are three types of mAbs that are dependent upon how they are administered or used: unconjugated or naked, conjugated, and bispecific. Unconjugated mAbs Unconjugated mAbs or “naked” mAbs are those antibodies that function by themselves. These are the most commonly used in the treatment of cancer. In most cases, these molecules attach to antigens on cancer cells.9 This can illicit one of several responses, which can be that the person’s natural immune response against the cancer cells is enhanced. The mAb attracts immune cells and aids in enhancing the recognition of cancer cells by the immune system, leading to increased apoptosis.9 Another mechanism is the targeting of immune system checkpoints, while other unconjugated mAbs block antigens on cancers that help them to expand and proliferate.9 Conjugated mAbs When an mAb is combined with a chemotherapy agent or with a radioactive particle it is referred to as a conjugated monoclonal antibody. The mAb serves as a delivery mechanism for the chemotherapy or radioactive particle, circulating through the patient’s body until it finds the intended target antigen.9 This method helps to minimize harm to normal cells by the chemotherapy agents or radioactive particle attached to the mAb.
Humanized Bispecific mAbs Humanized mAbs are created by grating the murine hypervariable regions of the light and heavy chains onto a human Ab framework.6,7 This results in molecules that are approximately 95% human. This resulted in decreased production of anti-drug antibodies. However, the process to create these molecules is arduous and has limitations.
This unique type of mAb is a combination of two different mAbs which allows for the mAb to attach to two different antigens at the same time. One target is the protein found on cancer cells, and the other target is a protein found on immune cells. This combination
Table 1 Types of monoclonal antibodies. Type
Key Concepts
Examples
Murine Ends in -omab
Uses harvested B lymphocytes from mice that are fused with an immortal myeloma cell line lacking the hypoxanthine-guanine-phosphoribosyltransferase gene Allergic reactions are common in humans, with potential limited benefit because of a short half-life Approximately 65% human derived, 35% murine derived, uses murine antigen-specific variable region, and heavy and light chains of human Demonstrate extended half-life in human with reduced immunogenicity; still able to induce antidrug antibodies Murine hypervariable regions of the light and heavy chains are fused onto a human Ab framework; approximately 95% human Has decreased production of anti-drug antibodies; limitations because the process to create is difficult Fully human monoclonal antibodies Less antigenic and better tolerated; appear to have the longest half-life in humans
Blinatumomab Moxetumomab pasudotox-tdfk
Chimeric Ends in -ximab
Humanized Ends in -zumab
Human Ends in -umab
Data from Buss et al6 and Garcia Merino.7
Cetuximab Rituximab
Alemtuzumab Ado-trastuzumab emtansine
Necitumumab Denosumab
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Fig. 1. Structure of monoclonal antibody.8
allows for the immune cell and cancer cell to be brought together, in hopes of inciting an increased immune response and the destruction of cancer cells.9 Mechanism of action The understanding of how these antibodies target cancer cells has helped to revolutionize the methods used to treat cancer and resulted in a more tolerable toxicity profile than standard chemotherapy. When utilizing mAbs in oncology, several mechanisms of action exist to destroy the cancer cells (Fig. 2). These mechanisms include impeding tumor cell survival cascades, inhibiting tumor growth by interfering with tumor angiogenesis, eluding programmed cell death, and evading immune checkpoints. Some of the different mechanisms of action include the following:10 Direct tumor cell killing This action is stimulated by receptor agonist activity, such as an antibody binding to a tumor cell surface receptor and activating it, leading to cell death. It can also be stimulated by receptor antagonist activity “such as an antibody binding to a cell surface receptor and blocking dimerization, kinase activation, and downstream signaling, leading to reduced proliferation and apoptosis.”9 A mAb binding to an enzyme can lead to neutralization and apoptosis, while conjugated antibodies can be used to deliver a payload, such as a drug, to the tumor cell.
a) b) c) d)
Phagocytosis; complement activation; antibody-dependent cellular cytotoxicity (ADCC); genetically modified T cells being targeted to the tumor by single-chain variable fragment; e) T cells being activated by antibody-mediated cross-presentation of antigen to dendritic cells; or f) inhibition of T-cell inhibitory receptors.10
Vascular and stromal cell ablation This action is also initiated by one of many options. These include: a) b) c) d)
vasculature receptor antagonism or ligand trapping; stromal cell inhibition; delivery of a toxin to stromal cells; or delivery of a toxin to the vasculature.10
Indications for Use and Administration Indications for mAbs in oncology include both solid tumor and hematologic malignancies. mAbs may be administered intravenously as well as subcutaneously. See Table 1 for specific indications and drug-specific administration guidelines. Toxicities
Immune-mediated tumor cell killing In this setting, the immune system will seek out cancer cells and destroy them. This type of cell death may be carried out by the initiation of one of several mechanisms. These mechanisms include:
Adverse reactions to mAbs are most often experienced by treatment-naïve patients. While anaphylactic reactions are rare with mAbs, hypersensitivity can occur. While anaphylaxis reactions affecting many organs can occur, what is most typically observed is
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Fig. 2. Mechanism of action of monoclonal antibody.8
a hypersensitivity that affects a “single organ such as the nasopharynx (allergic rhinitis), eyes (conjunctivitis), mucosa of mouth/ throat/tongue (angioedema), bronchopulmonary tissue (asthma), gastrointestinal tract (gastroenteritis), or skin (urticaria, eczema).”11 Another frequent adverse event that occurs during infusion is the standard infusion reaction. This reaction is demonstrated frequent enough with the administration of some mAbs that special precautions are instituted during infusion. The standard infusion reaction is usually mild and can manifest as dyspnea, nausea, headache, or abdominal pain.11 Additional drug-specific toxicities are listed in Table 2.12 14
Implications for Nursing Practice It is the position of the Oncology Nursing Society that any nurse who is administering and caring for patients receiving chemotherapy and biotherapy agents, including mAbs, should “hold fundamental knowledge of the agents being received by patients, including, but not limited to, mechanisms of action, pharmacologic and administration principles, indications for treatment, expected toxicities and adverse events, assessment and management recommendations, and a process to ensure patient safety.”15 The specific education and training required by those nurses administering these agents should be determined by the institution where the agent is being administered. Additional recommendations for practice and administration of mAbs are outlined in the Oncology Nursing Society’s Chemotherapy and Immunotherapy Guidelines and Recommendations for Practice.14 Collaboration with infection control should also be considered for nurses administering these agents to assist with the development of policies and procedures for their safe handling.
Additionally, for patient safety, mAbs should be verified before patient administration with the two-RN sign-off process, in accordance with the American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Standards for chemotherapy agents.9 The updated standards include mAbs in their definition of chemotherapy. As stated in ONS Voice, this secondstep verification will reduce potential mistakes in practice, enhancing patient safety.16 Patient Education Because the side effects related to the administration of mAbs vary depending on the intended target of the molecule and classification, it is important to educate your patients prior to the administration what potential side effects are and what is important to report immediately. Side effects can vary from fever to anaphylaxis, can be immediate or delayed, and may be mild or emergent. Therefore, preparing the patient, including the administration of appropriate premedications and educating them, is vital to their safety. Patients should be educated that they are receiving immunotherapy, specifically what type of monoclonal antibody they are receiving, and they should be instructed to provide this information to any provider they are interacting with when seeking treatment for symptoms.17 Conclusion mAbs offer alternative treatment to cancer patients who have failed or progressed on standard chemotherapy. The discovery of these molecules has revolutionized the battle against cancer, allowing for more direct approaches to killing cancer cells by targeting specific antigens on those cells. Clinical research continues to explore new antigens to
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Table 2 FDA approved monoclonal antibodies for use in oncology. Drug Blinatumomab Classification: Murine Type: Bi-specific
Moxetumomab pasudotox-tdfk Classification: Murine Type: Conjugated
Brentuximab vedotin Classification: Chimeric Type: Conjugated
Cetuximab Classification: Chimeric Type: Unconjugated
Dinituximab Classification: Chimeric Type: Unconjugated
Rituximab Classification: Chimeric Type: Unconjugated
Rituximab and hyaluronidase Classification: Chimeric Type: Conjugated
Indication
Mechanism of Action
Administration and Nursing Side Effects Considerations Continuous IV for 28 days; Edema, hypertension, neurotoxPhiladelphia chromosome-nega- Binds to CD19 on precursor B administer 5 28 mcg/m2 IV icity, headache, rash, hypokative relapsed or refractory ALL cells and to CD3 on the surface lemia, nausea, vomiting, of the T cells based on weight and cycle abdominal pain, pancytopenia, Premedicate with dexamethafebrile neutropenia, fever, elesone to minimize infusionvated ALT, infusion-related related reaction reaction Patients should be hospitalized for the first 9 days of the first cycle and first 2 days of the second cycle Instruct patients to refrain from driving while blinatumomab is infusing because of potential of neurotoxicity Capillary leak syndrome, hemoRelapsed or refractory Hairy cell Binds to CD22 and releases pseu- IV; administer 0.04 mg/kg per lytic uremic syndrome, infudose on Days 1, 3, and 5 of leukemia domonas exotoxin-A into the sion-related reactions, each 28-day cycle, maximum cancer cell peripheral edema peripheral, of 6 cycles nausea, fatigue, headache, Instruct patients to adequate fever, constipation, anemia, hydrate at minimum on Days diarrhea, hypertension, febrile 1 8 of each cycle neutropenia, elevated creatiMonitor fluid balance and nine, ALT, bilirubin, and AST, serum electrolytes to avoid hypoalbuminemia, hypomagfluid overload and/or electronesemia, platelet count lyte abnormalities decreased, hyperuricemia, and alkaline phosphate increased Peripheral neuropathy, fatigue, IV; recommended dosage is Targets the CD30 antigen and Relapsed or refractory Hodgkin rash, GI toxicities, neutrope1.8 mg/kg up to 180 mg IV delivers a drug called MMAE lymphoma; systemic anaplasnia, anemia, upper respiratory over 30 minutes every 3 (monomethyl auristatin E) tic large cell lymphoma; infection, cough, fever, infuweeks CD30-expressing mycosis funsion-related reactions Monitor liver enzymes and bilgoides (NHL) irubin; dose reduce in patients with mild hepatic impairment Colorectal cancer; head and neck Blocks the binding of ligands to IV; administer 400 mg/m2 initial Fatigue, pain, peripheral neuropcancers EGFR athy, headache, insomnia, dose as a 120-minute IV infuweight loss, skin toxicities, sion electrolyte disturbances, GI Premedicate with an H1 antagtoxicities, elevated LFTs, weakonist ness, cough, dyspnea, fever, Monitor serum electrolytes; pharyngitis, infusion-related monitor for dermatologic toxreactions icities and advise patients to wear sunscreen; monitor for new or worsening cardiac symptoms Neuroblastoma Binds to GD2 on neuroblastoma IV; administer 17.5 mg/m2 over Hypotension, capillary leak syncells, resulting in cell lysis drome, pain, urticaria, electro10 20 hours for 4 consecutive lyte imbalances, vomiting, days for up to 5 cycles diarrhea, pancytopenia, severe Premedicate with an analgesic, infusion-related reactions, antiemetic, antihistamine, fever, hypoxia antipyretic, and IV hydration with normal saline Monitor peripheral blood counts and serum electrolytes CLL; NHL Binds to the antigen CD20 IV; dosing dependent upon dis- Fatigue, chills, neuropathy, nausea, lymphocytopenia, anemia, ease and cycle infection, weakness, infusionPretreat with acetaminophen related reactions, tumor lysis and an antihistamine before syndrome each infusion Monitor renal function and CBC Advise patients to avoid vaccines Neutropenia, anemia, hypersenCLL; NHL Binds to the antigen CD20 and is SC; first dose of rituximab is sitivity reaction, nausea, congiven IV before beginning SC combined with hyaluronidase stipation, diarrhea, fatigue, dosing human tumor lysis syndrome, bowel Dosing dependent on disease; obstruction or perforation SC injections given over several minutes Premedicate with acetaminophen and an antihistamine before each infusion (continued)
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V. Bayer / Seminars in Oncology Nursing 35 (2019) 150927 Daratumumab Classification: Human Type: Unconjugated
Multiple myeloma
Binds to CD38
Denosumab Classification: Human Type: Unconjugated
Bone metastasis
Binds to RANKL and blocks its interaction with RANK
Necitumumab Classification: Human Type: Unconjugated
Lung cancer
Binds to and prevents the ligand binding of EGFR
Ofatumumab Classification: Human Type: Unconjugated
Previously untreated CLL, relapsed/refractory CLL
Binds to CD20 antigen on B cells
Olaratumab Classification: Human Type: Unconjugated
Sarcoma
Binds to PDGFR-a, blocking it
Panitumumab Classification: Human Type: Unconjugated
Colorectal cancer
Ramucirumab Classification: Human Type: Unconjugated
Colorectal cancer; lung cancer; gastric cancer
Ado-trastuzumab emtansine Classification: Humanized Type: Conjugated
HER2-positive metastatic breast cancer
Alemtuzumab Classification: Humanized Type: Unconjugated
Leukemia
Bevacizumab Classification: Humanized Type: Unconjugated
Multiple solid tumor cancers (breast, cervical, colorectal, glioblastoma, lung, ovarian,
IV; administer 16 mg/kg weekly for 8 doses, then every 2 weeks through week 24 and then every 4 weeks Pretreat with dexamethasone, antipyretic, and antihistamine May cause a positive indirect Coombs test; all patients should have a type and screen before starting therapy Educate patient to monitor for signs of infection and easy bleeding SC; administer SC 120 mg every 4 weeks Monitor calcium levels Assess for and advise patients to report symptoms of osteonecrosis of the jaw or hypocalcemia IV; administer 800 mg as an IV infusion over 60 minutes on days 1 and 8 of each 21-day cycle Monitor serum electrolytes Advise patients to report symptoms of thromboembolic events and hypomagnesemia Patients should be educated to wear sunscreen IV; dose is dependent on stage and treatment history Monitor CBC and neurologic function Patients should report any signs of infection IV; administer at 15 mg/kg over 60 minutes on Days 1 and 8 of each 21-day cycle Premedicate with antihistamine before drug administration on Day 1 of Cycle 1
Fatigue, nausea, lymphocytopenia, neutropenia, anemia, back pain, cough, fever, infusionrelated reactions
Osteonecrosis of the jaw, hypocalcemia, hypophosphatemia, dyspnea, infusion-related reactions
Skin toxicity, rash, hypomagnesemia, hypocalcemia, hypophosphatemia, hypokalemia, vomiting, infusion-related reactions
Neutropenia, infection, pneumonia, reactivation of hepatitis B virus, infusion-related reactions
Fatigue, neuropathy, alopecia, nausea, mucositis, vomiting, diarrhea, abdominal pain, anorexia, musculoskeletal pain, neutropenia, hyperglycemia, electrolyte imbalances, infusion-related reactions IV; administer 6 mg/kg every 14 Fatigue, skin toxicity (very comBlocks the binding of ligands to mon), ocular toxicity, nausea, EGFR days diarrhea, vomiting, dyspnea, Monitor electrolytes and ocupulmonary fibrosis/interstitial lar toxicities lung diseases, infusion-related Advise patient to limit sun reactions exposure Binds to VEGFR2 and prevents IV; administer 8 10 mg/kg infu- Hypertension, proteinuria, infuligands from binding sion over 60 minutes; schedsion-related reactions ule is specific to cancer type Premedicate with H1 antagonist Monitor blood pressure, urine protein levels, and thyroid function Fatigue, headache, peripheral Targets HER2 and delivers DM-1 IV; Administer 3.6 mg/kg every neuropathy, pancytopenia, GI to cancer cells 21 days toxicities, hypokalemia, hemMonitor platelet counts orrhage, elevated LFTs, myalMonitor for signs of neurotoxgias, epistaxis, infusionicity, acute hepatotoxicity related reactions Targets the CD52 antigen on leu- IV; initiate at a dose of 3 mg over Headache, fatigue, rash, thyroid disease, nausea, lymphocytokemia cells 2 hours daily; dose can be penia, antibody development, escalated up to 30 mg daily as infection, infusion-related tolerated reaction, nasopharyngitis, Premedicate with antihistafever mine and acetaminophen, with or without infectives Determine history of varicella or varicella zoster virus vaccination before dose administration Monitor CBC and platelets Hypertension, fatigue, pain, IV; administer 5 10 mg/kg Binds to VEGF and prevents it headache, abdominal pain, every 2 3 weeks depending from binding with its constipation, diarrhea, nausea, on cancer type receptors vomiting, anorexia, Monitor blood pressure and (continued)
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hemorrhage, leukopenia, urine protein, signs of GI perupper respiratory tract infecforation tion, dyspnea, infusion-related Advise patients to use reliable reactions contraception IV; administer 10 mg/kg every Multiple myeloma Binds to SLAMF7 on myeloma Bradycardia, tachycardia, altered week for first 2 cycles, then cells and activates NK cell blood pressure, fatigue, every 2 weeks thereafter cytotoxicity peripheral neuropathy, hyperPremedicate with an antihistaglycemia, decreased serum mine, H2 antagonist, acetbicarbonate, hyperkalemia, diarrhea, constipation, aminophen, and anorexia, lymphocytopenia, dexamethasone leukopenia, thrombocytopeMonitor LFTs nia, elevated alkaline phosInstruct patients to reports phatase, infection, cough, signs of infection or electrolyte pneumonia, fever, infusionimbalance related reactions CD33-positive acute myeloid Binds to CD33 on leukemia cells IV; administer 2 6 mg/kg over 2 Abdominal pain, anorexia, fever, chills, constipation, diarrhea, leukemia hours dyspnea, esophagitis, headPremedicate with acetaminoache, hyperbilirubinemia, phen and an antihistamine hypokalemia, infections, nauMonitor platelet counts sea, mucositis, vomiting, Advise patients to report signs weakness, infusion-related of infection, GI toxicities, and reaction hypokalemia Relapsed or refractory B-cell pre- Binds to CD22 and delivers a IV; administer over 1 hour: Myelosuppression, infusion2 Day 1: 0.8 mg/m cursor ALL in adults cytotoxic agent to the cancer related reactions, QT interval Day 8: 0.5 mg/m2 cell prolongation, embryo-fetal Day 15: 0.5 mg/m2 toxicity, liver toxicity, fatigue Premedicate with corticosteroid, antipyretic, and antihistamine Monitor for at least 1 hour post-infusion for infusionrelated reactions Leukemia, lymphoma Binds to CD20, eventually leadIV; administer for 6 cycles, dose Hypophosphatemia, hypocalcemia, hyperkalemia, hyponatreing to cell death varies on day and cycle mia, hypoalbuminemia, Premedicate with acetaminoleukopenia, elevated LFTs, phen, dexamethasone, and an anemia, infection, decreased antihistamine for Cycle 1 creatinine clearance, cough, Monitor CBC and electrolytes infusion-related reactions Patients should avoid live vaccines and should monitor for kidney or liver dysfunction Weakness, myalgias, neutropeBreast cancer Targets HER2 protein on breast IV; administer initial dose of nia, anemia, diarrhea, nausea, cancer cells 840 mg over 60 minutes, then vomiting, alopecia, rash, 420 mg every 3 weeks fatigue, headache, left ventricMonitor LVEF for cardiac failular cardiac dysfunction, infuure/dysfunction symptoms sion-related reactions Decreased LVEF, pain, chills, IV; administer initial dose of Breast cancer, gastric cancer Targets HER2 protein and supheadache, diarrhea, nausea, 2 8 mg/kg, dependent upon presses cancer cell growth and vomiting, abdominal pain, cancer type proliferation weakness, cough, dyspnea, Monitor LVEF and for cardiac fever, infusion-related failure/dysfunction symptoms reactions Hematologic toxicity, fatigue, Relapsed or refractory follicular Binds to the CD20 antigen found IV; administered on a specific nasopharyngitis, nausea, regiment that includes “preon B cells, allowing radiation B-cell or low-grade NHL, follicabdominal pain, asthenia, targeting” of the tissues with from the attached isotope to ular lymphoma in patients cough, diarrhea, fever, secondthe mAb rituximab first destroy the cancer cells and who achieved a complete or ary leukemias, severe infuMonitor CBC weekly for up to those in the immediate partial response to first-line sion-related reactions, severe 3 months after administration proximity chemotherapy cutaneous and mucocutaneous Instruct patients to use effecreactions (erythema multitive contraception methods forme, Stevens-Johnson synduring treatment and for 12 drome, toxic epidermal months post-administration necrolysis, dermatitis) Instruct patients not to receive live vaccines renal cell cancer, primary peritoneal, fallopian tube)
Elotuzumab Classification: Humanized Type: Unconjugated
Gemtuzumab ozogamicin Classification: Humanized Type: Conjugated
Inotuzumab ozogamicin Classification: Humanized Type: Conjugated
Oblinutuzumab Classification: Humanized Type: Unconjugated
Pertuzumab Classification: Humanized Type: Unconjugated
Trastuzumab Classification: Humanized Type: Unconjugated
Y-ibrutumomab tiuxetan Classification: Murine Type: Radioimmunotherapy/ conjugated
Abbreviations: ALL, acute lymphoblastic leukemia; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CLL, chronic lymphocytic leukemia; CBC, complete blood count; EGFR, epidermal growth factor receptor; GI, gastrointestinal; IV, intravenous; LFT, liver function test; LVEF, left ventricular ejection fraction; NHL, non-Hodgkin lymphoma; SC, subcutaneous Data from AstraZeneca,11 National Cancer Institute,12 and Olsen et al.13
target in hopes of discovering the “magic bullet” that will eliminate cancer altogether. While the associated side effects can be significantly less toxic than that of traditional chemotherapy, these agents can still pose a significant risk to patients. Therefore, nurses play a vital role in communicating with the other care team members and providing adequate patient education to ensure patient safety.
References 1. Mayo Clinic Staff. 2018. Monoclonal antibody drugs for cancer: how they work. Available at: https://www.mayoclinic.org/diseases-conditions/cancer/in-depth/ monoclonal-antibody/art-20047808 (Accessed 03/27/2019). 2. Pandey M, Mahadevan D. Monoclonal antibodies as therapeutics in human malignancies. Future Oncol. 2014;10:609–636.
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3. Kaunitz J. Development of monoclonal antibodies: the dawn of mAb rule. Dig Dis Sci. 2017;62:831–832. 4. Liu J. The history of monoclonal antibody development progress, remaining challenges and future innovations. Ann Med Sci. 2014;3:113–116. 5. Shepard HM, Phillips GL, Thanos CD, Feldmann MD. Developments in therapy with monoclonal antibodies and related proteins. Clin Med (Lond). 2017;17:220–232. 6. Buss NA, Henderson SJ, McFarlane M, Shenton JM, de Haan L. Monoclonal antibody therapeutics: History and future. Curr Opin Pharmacol. 2012;12:615–622. 7. Garcia Merino A. Monoclonal antibodies basic features. Neurologia. 2010;26:301–306. 8. Modjtahedi H, Essapen S. Therapeutic application of monoclonal antibodies in cancer: advances and challenges. Br Med Bull. 2012;104:41–59. 9. American Cancer Society. Monoclonal antibodies to treat cancer. 2016. Available at: https://www.cancer.org/treatment/treatments-and-side-effects/treatmenttypes/immunotherapy/monoclonal-antibodies.html. (Accessed 03/27/19). 10. Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012;12: 278–287.
11. Guan M, Zhou Y, Sun J, Chen S. Adverse events of monoclonal antibodies used for cancer therapy. BioMed Res Int. 2015;15:1–13. 12. AstraZeneca. Lumoxiti for healthcare professionals. 2019. Available at: https:// www.lumoxitihcp.com/. (Accessed 03/27/2019). 13. National Cancer Institute. Brentuximab vedotin approved for two rare lymphomas. 2017. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/ 2017/brentuximab-fda-rare-lymphomas. (Accessed 03/27/2019). 14. Olsen M, LeFebvre K, Brassil K. Chemotherapy and Immunotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA; Oncology Nursing Society. 15. Wiley K, LeFebvre K, Wall L, et al. Immunotherapy administration: Oncology Nursing Society recommendations. Clin J Oncol Nurs. 2017;21:5–7. 16. Pirschel C. Monoclonal antibodies should have 2-RN verification. ONS Voice. 2017;32:39. 17. Bohnenkamp S. Immuno-oncology: another option for treatment of cancer. MedSurg Nurs. 2018;27:336–339.
Contents lists available at ScienceDirect
Seminars in Oncology Nursing journal homepage: https://www.journals.elsevier.com/seminars-in-oncology-nursing
An Overview of Monoclonal Antibodies Virginia Bayer, BSN, RN, OCNÒ ,* Department of Gynecology Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston TX
A R T I C L E
I N F O
Article History: Available online xxx Keywords: monoclonal antibodies (mAb) cancer murine chimeric immunotherapy
A B S T R A C T
Objective: To provide a brief overview of the development of monoclonal antibodies in immunotherapy, including a review of the mechanism of action and types, and indications for use. Data Source: Peer-reviewed journal articles, book chapters, internet. Conclusion: Monoclonal antibodies offer alternative treatment to cancer patients who have failed or progressed on standard chemotherapy. Clinical research continues to explore new antigens to target in hopes of discovering the “magic bullet” to eliminate cancer altogether. Implications for Nursing Practice: Collaboration with infection control should be considered for nurses administering monoclonal antibodies to ensure their safe handling. These agents should be verified before administration with the two-RN sign-off system. Nurses play a vital role in providing adequate patient education to ensure patient safety. © 2019 Elsevier Inc. All rights reserved.
History Monoclonal antibodies (mAbs) are defined as “laboratory-produced molecules engineered to serve as substitute antibodies that can restore, enhance, or mimic the immune system's attack on cancer cells” by binding to antigens found on the surface of cancer cells.1 Experiments to create this type of treatment have existed for more than a century.2 In the 18th century, it was discovered by Dr Edward Jenner that “fluid obtained from a smallpox pustule when injected into a recipient provided immunity from acquiring the disease.”3 This was part of the beginning stages of antibody development. In the 1930s and 1940s, several scientists’ work contributed to the concept of mAbs, including the isolation of agglutin from lymph nodes by McMaster and Hudack and the identification that lymphocytes are the source of antibody production.3 The earliest antibodies were traditionally created by “immunizing experimental animals with an antigen with subsequent purification of the serum to isolate the antibody fraction.”3 The first description of laboratory created mAbs was published in 1970, describing the technique of how a single plasma cell clone was isolated, which generated a homogenous antibody, proliferated by repeated passage of spleen cells into irradiated syngeneic mice. However, the first monoclonal antibody for human use was not generated until 1975, and the first monoclonal antibody was not fully licensed until 1986.4 Milstein and Kohler won the Nobel Prize in Physiology or Medicine in 1984,
* Address correspondence to: Virginia Bayer, BSN, RN, OCNÒ , Department of Gynecology Oncology & Reproductive Medicine, MD Anderson Cancer Center, Unit 1362, P. O. Box 301439, Houston, TX 77230-1439. E-mail address: [email protected] https://doi.org/10.1016/j.soncn.2019.08.006 0749-2081/© 2019 Elsevier Inc. All rights reserved.
being the first to be able to reproduce large amounts of mAbs in vivo.5 This was the birth of the “hybridoma’’ and the practice of producing mAbs was changed forever. The initial mAbs were generated utilizing murine (from mice) protein and were not well tolerated for long periods of time by humans. Therefore, the production mechanisms were forced to be reevaluated and eventually changed by the development of technology, allowing for fully humanized antibodies. The first monoclonal antibody to be approved by the US Food and Drug Administration was muromonab-CD3, which was used as an anti-rejection medication.3 The first monoclonal antibody that was found successful in the treatment of solid tumors was trastuzumab. This mAb was initiated by the humanized human epidermal growth factor receptor 2 (HER2).5 The laborious science that brought about trastuzumab also led to the beginning of drug discovery and treatment in cancer targeting a patient’s unique biomarkers. Pathophysiology The production and release of antibodies by plasma cells is part of the body’s normal immune response to a foreign substance or toxin. Scientists developed a method to engineer antibodies as a method of targeting cancer cells. Monoclonal antibodies, also known as mAbs, are substances developed in a laboratory that seek out and bind to specifically selected proteins wherever they may be in the body. The mAbs are structured by the binding of two heavy and two light polypeptide chains by a disulfide bond. The resultant “Y” formation includes the variable or “Fab” region, which varies according to the antigen being bound to it, and the “Fc” or constant region of the antibody, which is responsible for linking the antibody with cells
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involved in the immune response.6 Depending upon which antigen is bound to the antibody and the Fc region, an antibody-dependent cell cytotoxicity or complement-system cytotoxicity can be generated. This can result in the blocking of cell membrane receptors and inhibiting intracellular signals.7 Classification and Types of mAbs There are four classifications of mAbs: murine, chimeric, humanized, and human (see Table 1).6,7 The structure of mAbs is depicted in Figure 1.8 Murine The first mAb to be discovered and reproduced was the murine monoclonal antibody. This type of mAb arises from harvesting B lymphocytes from the spleen of a mice and then fused with an immortal myeloma cell line lacking the hypoxanthine-guanine-phosphoribosyltransferase (HPTR) gene.4 All of these mAbs are identified with a name that ends in -omab (ie, muromonab-CD3, blinatumomab, capromab). Allergic reactions are common when used in humans and often result in the induction of anti-drug antibodies. Murine mAbs also have a short half-life when used in humans because of a relatively weak binding to the human FcRn.6 For oncology, these mAbs may not be the most beneficial as they are “relatively poor recruiters of effector function, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity,” essential functions needed for tumor destruction.6 Chimeric Chimeric mAbs utilize the murine antigen-specific variable region, but the remaining heavy and light chains are human.7 This was accomplished using genetic engineering techniques, which resulted in mAbs that are approximately 65% human and 35% murine.6 The chimeric mAbs are identified with names ending in -ximab (ie, rituximab, infliximab, cetuximab). Compared with their murine counterparts, these mAbs “exhibit an extended half-life in man and show reduced immunogenicity, but nevertheless, the propensity of chimeric mAbs to induce anti-drug antibodies is still considerable.”6
These mAbs are identified with names ending in -zumab (ie, trastuzumab, alemtuzumab, bevacizumab). Human With the development of new technology, fully human mAbs were able to be created. These are created utilizing animals carrying human Ig genes. These transgenes include parts of the variable regions, which enable the recombination of the human antibodies.7 The animal’s own endogenous Ig genes have been inactivated, enabling the generation of fully human mAbs. These mAbs are less antigenic and better tolerated compared with the other classes of mAbs. Additionally, they appear to remain present in the human body’s circulation compared with the other classes.6 These mAbs are identified with names ending in -umab (ie, ofatumumab, daratumumab, denosumab). There are three types of mAbs that are dependent upon how they are administered or used: unconjugated or naked, conjugated, and bispecific. Unconjugated mAbs Unconjugated mAbs or “naked” mAbs are those antibodies that function by themselves. These are the most commonly used in the treatment of cancer. In most cases, these molecules attach to antigens on cancer cells.9 This can illicit one of several responses, which can be that the person’s natural immune response against the cancer cells is enhanced. The mAb attracts immune cells and aids in enhancing the recognition of cancer cells by the immune system, leading to increased apoptosis.9 Another mechanism is the targeting of immune system checkpoints, while other unconjugated mAbs block antigens on cancers that help them to expand and proliferate.9 Conjugated mAbs When an mAb is combined with a chemotherapy agent or with a radioactive particle it is referred to as a conjugated monoclonal antibody. The mAb serves as a delivery mechanism for the chemotherapy or radioactive particle, circulating through the patient’s body until it finds the intended target antigen.9 This method helps to minimize harm to normal cells by the chemotherapy agents or radioactive particle attached to the mAb.
Humanized Bispecific mAbs Humanized mAbs are created by grating the murine hypervariable regions of the light and heavy chains onto a human Ab framework.6,7 This results in molecules that are approximately 95% human. This resulted in decreased production of anti-drug antibodies. However, the process to create these molecules is arduous and has limitations.
This unique type of mAb is a combination of two different mAbs which allows for the mAb to attach to two different antigens at the same time. One target is the protein found on cancer cells, and the other target is a protein found on immune cells. This combination
Table 1 Types of monoclonal antibodies. Type
Key Concepts
Examples
Murine Ends in -omab
Uses harvested B lymphocytes from mice that are fused with an immortal myeloma cell line lacking the hypoxanthine-guanine-phosphoribosyltransferase gene Allergic reactions are common in humans, with potential limited benefit because of a short half-life Approximately 65% human derived, 35% murine derived, uses murine antigen-specific variable region, and heavy and light chains of human Demonstrate extended half-life in human with reduced immunogenicity; still able to induce antidrug antibodies Murine hypervariable regions of the light and heavy chains are fused onto a human Ab framework; approximately 95% human Has decreased production of anti-drug antibodies; limitations because the process to create is difficult Fully human monoclonal antibodies Less antigenic and better tolerated; appear to have the longest half-life in humans
Blinatumomab Moxetumomab pasudotox-tdfk
Chimeric Ends in -ximab
Humanized Ends in -zumab
Human Ends in -umab
Data from Buss et al6 and Garcia Merino.7
Cetuximab Rituximab
Alemtuzumab Ado-trastuzumab emtansine
Necitumumab Denosumab
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Fig. 1. Structure of monoclonal antibody.8
allows for the immune cell and cancer cell to be brought together, in hopes of inciting an increased immune response and the destruction of cancer cells.9 Mechanism of action The understanding of how these antibodies target cancer cells has helped to revolutionize the methods used to treat cancer and resulted in a more tolerable toxicity profile than standard chemotherapy. When utilizing mAbs in oncology, several mechanisms of action exist to destroy the cancer cells (Fig. 2). These mechanisms include impeding tumor cell survival cascades, inhibiting tumor growth by interfering with tumor angiogenesis, eluding programmed cell death, and evading immune checkpoints. Some of the different mechanisms of action include the following:10 Direct tumor cell killing This action is stimulated by receptor agonist activity, such as an antibody binding to a tumor cell surface receptor and activating it, leading to cell death. It can also be stimulated by receptor antagonist activity “such as an antibody binding to a cell surface receptor and blocking dimerization, kinase activation, and downstream signaling, leading to reduced proliferation and apoptosis.”9 A mAb binding to an enzyme can lead to neutralization and apoptosis, while conjugated antibodies can be used to deliver a payload, such as a drug, to the tumor cell.
a) b) c) d)
Phagocytosis; complement activation; antibody-dependent cellular cytotoxicity (ADCC); genetically modified T cells being targeted to the tumor by single-chain variable fragment; e) T cells being activated by antibody-mediated cross-presentation of antigen to dendritic cells; or f) inhibition of T-cell inhibitory receptors.10
Vascular and stromal cell ablation This action is also initiated by one of many options. These include: a) b) c) d)
vasculature receptor antagonism or ligand trapping; stromal cell inhibition; delivery of a toxin to stromal cells; or delivery of a toxin to the vasculature.10
Indications for Use and Administration Indications for mAbs in oncology include both solid tumor and hematologic malignancies. mAbs may be administered intravenously as well as subcutaneously. See Table 1 for specific indications and drug-specific administration guidelines. Toxicities
Immune-mediated tumor cell killing In this setting, the immune system will seek out cancer cells and destroy them. This type of cell death may be carried out by the initiation of one of several mechanisms. These mechanisms include:
Adverse reactions to mAbs are most often experienced by treatment-naïve patients. While anaphylactic reactions are rare with mAbs, hypersensitivity can occur. While anaphylaxis reactions affecting many organs can occur, what is most typically observed is
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Fig. 2. Mechanism of action of monoclonal antibody.8
a hypersensitivity that affects a “single organ such as the nasopharynx (allergic rhinitis), eyes (conjunctivitis), mucosa of mouth/ throat/tongue (angioedema), bronchopulmonary tissue (asthma), gastrointestinal tract (gastroenteritis), or skin (urticaria, eczema).”11 Another frequent adverse event that occurs during infusion is the standard infusion reaction. This reaction is demonstrated frequent enough with the administration of some mAbs that special precautions are instituted during infusion. The standard infusion reaction is usually mild and can manifest as dyspnea, nausea, headache, or abdominal pain.11 Additional drug-specific toxicities are listed in Table 2.12 14
Implications for Nursing Practice It is the position of the Oncology Nursing Society that any nurse who is administering and caring for patients receiving chemotherapy and biotherapy agents, including mAbs, should “hold fundamental knowledge of the agents being received by patients, including, but not limited to, mechanisms of action, pharmacologic and administration principles, indications for treatment, expected toxicities and adverse events, assessment and management recommendations, and a process to ensure patient safety.”15 The specific education and training required by those nurses administering these agents should be determined by the institution where the agent is being administered. Additional recommendations for practice and administration of mAbs are outlined in the Oncology Nursing Society’s Chemotherapy and Immunotherapy Guidelines and Recommendations for Practice.14 Collaboration with infection control should also be considered for nurses administering these agents to assist with the development of policies and procedures for their safe handling.
Additionally, for patient safety, mAbs should be verified before patient administration with the two-RN sign-off process, in accordance with the American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Standards for chemotherapy agents.9 The updated standards include mAbs in their definition of chemotherapy. As stated in ONS Voice, this secondstep verification will reduce potential mistakes in practice, enhancing patient safety.16 Patient Education Because the side effects related to the administration of mAbs vary depending on the intended target of the molecule and classification, it is important to educate your patients prior to the administration what potential side effects are and what is important to report immediately. Side effects can vary from fever to anaphylaxis, can be immediate or delayed, and may be mild or emergent. Therefore, preparing the patient, including the administration of appropriate premedications and educating them, is vital to their safety. Patients should be educated that they are receiving immunotherapy, specifically what type of monoclonal antibody they are receiving, and they should be instructed to provide this information to any provider they are interacting with when seeking treatment for symptoms.17 Conclusion mAbs offer alternative treatment to cancer patients who have failed or progressed on standard chemotherapy. The discovery of these molecules has revolutionized the battle against cancer, allowing for more direct approaches to killing cancer cells by targeting specific antigens on those cells. Clinical research continues to explore new antigens to
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Table 2 FDA approved monoclonal antibodies for use in oncology. Drug Blinatumomab Classification: Murine Type: Bi-specific
Moxetumomab pasudotox-tdfk Classification: Murine Type: Conjugated
Brentuximab vedotin Classification: Chimeric Type: Conjugated
Cetuximab Classification: Chimeric Type: Unconjugated
Dinituximab Classification: Chimeric Type: Unconjugated
Rituximab Classification: Chimeric Type: Unconjugated
Rituximab and hyaluronidase Classification: Chimeric Type: Conjugated
Indication
Mechanism of Action
Administration and Nursing Side Effects Considerations Continuous IV for 28 days; Edema, hypertension, neurotoxPhiladelphia chromosome-nega- Binds to CD19 on precursor B administer 5 28 mcg/m2 IV icity, headache, rash, hypokative relapsed or refractory ALL cells and to CD3 on the surface lemia, nausea, vomiting, of the T cells based on weight and cycle abdominal pain, pancytopenia, Premedicate with dexamethafebrile neutropenia, fever, elesone to minimize infusionvated ALT, infusion-related related reaction reaction Patients should be hospitalized for the first 9 days of the first cycle and first 2 days of the second cycle Instruct patients to refrain from driving while blinatumomab is infusing because of potential of neurotoxicity Capillary leak syndrome, hemoRelapsed or refractory Hairy cell Binds to CD22 and releases pseu- IV; administer 0.04 mg/kg per lytic uremic syndrome, infudose on Days 1, 3, and 5 of leukemia domonas exotoxin-A into the sion-related reactions, each 28-day cycle, maximum cancer cell peripheral edema peripheral, of 6 cycles nausea, fatigue, headache, Instruct patients to adequate fever, constipation, anemia, hydrate at minimum on Days diarrhea, hypertension, febrile 1 8 of each cycle neutropenia, elevated creatiMonitor fluid balance and nine, ALT, bilirubin, and AST, serum electrolytes to avoid hypoalbuminemia, hypomagfluid overload and/or electronesemia, platelet count lyte abnormalities decreased, hyperuricemia, and alkaline phosphate increased Peripheral neuropathy, fatigue, IV; recommended dosage is Targets the CD30 antigen and Relapsed or refractory Hodgkin rash, GI toxicities, neutrope1.8 mg/kg up to 180 mg IV delivers a drug called MMAE lymphoma; systemic anaplasnia, anemia, upper respiratory over 30 minutes every 3 (monomethyl auristatin E) tic large cell lymphoma; infection, cough, fever, infuweeks CD30-expressing mycosis funsion-related reactions Monitor liver enzymes and bilgoides (NHL) irubin; dose reduce in patients with mild hepatic impairment Colorectal cancer; head and neck Blocks the binding of ligands to IV; administer 400 mg/m2 initial Fatigue, pain, peripheral neuropcancers EGFR athy, headache, insomnia, dose as a 120-minute IV infuweight loss, skin toxicities, sion electrolyte disturbances, GI Premedicate with an H1 antagtoxicities, elevated LFTs, weakonist ness, cough, dyspnea, fever, Monitor serum electrolytes; pharyngitis, infusion-related monitor for dermatologic toxreactions icities and advise patients to wear sunscreen; monitor for new or worsening cardiac symptoms Neuroblastoma Binds to GD2 on neuroblastoma IV; administer 17.5 mg/m2 over Hypotension, capillary leak syncells, resulting in cell lysis drome, pain, urticaria, electro10 20 hours for 4 consecutive lyte imbalances, vomiting, days for up to 5 cycles diarrhea, pancytopenia, severe Premedicate with an analgesic, infusion-related reactions, antiemetic, antihistamine, fever, hypoxia antipyretic, and IV hydration with normal saline Monitor peripheral blood counts and serum electrolytes CLL; NHL Binds to the antigen CD20 IV; dosing dependent upon dis- Fatigue, chills, neuropathy, nausea, lymphocytopenia, anemia, ease and cycle infection, weakness, infusionPretreat with acetaminophen related reactions, tumor lysis and an antihistamine before syndrome each infusion Monitor renal function and CBC Advise patients to avoid vaccines Neutropenia, anemia, hypersenCLL; NHL Binds to the antigen CD20 and is SC; first dose of rituximab is sitivity reaction, nausea, congiven IV before beginning SC combined with hyaluronidase stipation, diarrhea, fatigue, dosing human tumor lysis syndrome, bowel Dosing dependent on disease; obstruction or perforation SC injections given over several minutes Premedicate with acetaminophen and an antihistamine before each infusion (continued)
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Multiple myeloma
Binds to CD38
Denosumab Classification: Human Type: Unconjugated
Bone metastasis
Binds to RANKL and blocks its interaction with RANK
Necitumumab Classification: Human Type: Unconjugated
Lung cancer
Binds to and prevents the ligand binding of EGFR
Ofatumumab Classification: Human Type: Unconjugated
Previously untreated CLL, relapsed/refractory CLL
Binds to CD20 antigen on B cells
Olaratumab Classification: Human Type: Unconjugated
Sarcoma
Binds to PDGFR-a, blocking it
Panitumumab Classification: Human Type: Unconjugated
Colorectal cancer
Ramucirumab Classification: Human Type: Unconjugated
Colorectal cancer; lung cancer; gastric cancer
Ado-trastuzumab emtansine Classification: Humanized Type: Conjugated
HER2-positive metastatic breast cancer
Alemtuzumab Classification: Humanized Type: Unconjugated
Leukemia
Bevacizumab Classification: Humanized Type: Unconjugated
Multiple solid tumor cancers (breast, cervical, colorectal, glioblastoma, lung, ovarian,
IV; administer 16 mg/kg weekly for 8 doses, then every 2 weeks through week 24 and then every 4 weeks Pretreat with dexamethasone, antipyretic, and antihistamine May cause a positive indirect Coombs test; all patients should have a type and screen before starting therapy Educate patient to monitor for signs of infection and easy bleeding SC; administer SC 120 mg every 4 weeks Monitor calcium levels Assess for and advise patients to report symptoms of osteonecrosis of the jaw or hypocalcemia IV; administer 800 mg as an IV infusion over 60 minutes on days 1 and 8 of each 21-day cycle Monitor serum electrolytes Advise patients to report symptoms of thromboembolic events and hypomagnesemia Patients should be educated to wear sunscreen IV; dose is dependent on stage and treatment history Monitor CBC and neurologic function Patients should report any signs of infection IV; administer at 15 mg/kg over 60 minutes on Days 1 and 8 of each 21-day cycle Premedicate with antihistamine before drug administration on Day 1 of Cycle 1
Fatigue, nausea, lymphocytopenia, neutropenia, anemia, back pain, cough, fever, infusionrelated reactions
Osteonecrosis of the jaw, hypocalcemia, hypophosphatemia, dyspnea, infusion-related reactions
Skin toxicity, rash, hypomagnesemia, hypocalcemia, hypophosphatemia, hypokalemia, vomiting, infusion-related reactions
Neutropenia, infection, pneumonia, reactivation of hepatitis B virus, infusion-related reactions
Fatigue, neuropathy, alopecia, nausea, mucositis, vomiting, diarrhea, abdominal pain, anorexia, musculoskeletal pain, neutropenia, hyperglycemia, electrolyte imbalances, infusion-related reactions IV; administer 6 mg/kg every 14 Fatigue, skin toxicity (very comBlocks the binding of ligands to mon), ocular toxicity, nausea, EGFR days diarrhea, vomiting, dyspnea, Monitor electrolytes and ocupulmonary fibrosis/interstitial lar toxicities lung diseases, infusion-related Advise patient to limit sun reactions exposure Binds to VEGFR2 and prevents IV; administer 8 10 mg/kg infu- Hypertension, proteinuria, infuligands from binding sion over 60 minutes; schedsion-related reactions ule is specific to cancer type Premedicate with H1 antagonist Monitor blood pressure, urine protein levels, and thyroid function Fatigue, headache, peripheral Targets HER2 and delivers DM-1 IV; Administer 3.6 mg/kg every neuropathy, pancytopenia, GI to cancer cells 21 days toxicities, hypokalemia, hemMonitor platelet counts orrhage, elevated LFTs, myalMonitor for signs of neurotoxgias, epistaxis, infusionicity, acute hepatotoxicity related reactions Targets the CD52 antigen on leu- IV; initiate at a dose of 3 mg over Headache, fatigue, rash, thyroid disease, nausea, lymphocytokemia cells 2 hours daily; dose can be penia, antibody development, escalated up to 30 mg daily as infection, infusion-related tolerated reaction, nasopharyngitis, Premedicate with antihistafever mine and acetaminophen, with or without infectives Determine history of varicella or varicella zoster virus vaccination before dose administration Monitor CBC and platelets Hypertension, fatigue, pain, IV; administer 5 10 mg/kg Binds to VEGF and prevents it headache, abdominal pain, every 2 3 weeks depending from binding with its constipation, diarrhea, nausea, on cancer type receptors vomiting, anorexia, Monitor blood pressure and (continued)
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hemorrhage, leukopenia, urine protein, signs of GI perupper respiratory tract infecforation tion, dyspnea, infusion-related Advise patients to use reliable reactions contraception IV; administer 10 mg/kg every Multiple myeloma Binds to SLAMF7 on myeloma Bradycardia, tachycardia, altered week for first 2 cycles, then cells and activates NK cell blood pressure, fatigue, every 2 weeks thereafter cytotoxicity peripheral neuropathy, hyperPremedicate with an antihistaglycemia, decreased serum mine, H2 antagonist, acetbicarbonate, hyperkalemia, diarrhea, constipation, aminophen, and anorexia, lymphocytopenia, dexamethasone leukopenia, thrombocytopeMonitor LFTs nia, elevated alkaline phosInstruct patients to reports phatase, infection, cough, signs of infection or electrolyte pneumonia, fever, infusionimbalance related reactions CD33-positive acute myeloid Binds to CD33 on leukemia cells IV; administer 2 6 mg/kg over 2 Abdominal pain, anorexia, fever, chills, constipation, diarrhea, leukemia hours dyspnea, esophagitis, headPremedicate with acetaminoache, hyperbilirubinemia, phen and an antihistamine hypokalemia, infections, nauMonitor platelet counts sea, mucositis, vomiting, Advise patients to report signs weakness, infusion-related of infection, GI toxicities, and reaction hypokalemia Relapsed or refractory B-cell pre- Binds to CD22 and delivers a IV; administer over 1 hour: Myelosuppression, infusion2 Day 1: 0.8 mg/m cursor ALL in adults cytotoxic agent to the cancer related reactions, QT interval Day 8: 0.5 mg/m2 cell prolongation, embryo-fetal Day 15: 0.5 mg/m2 toxicity, liver toxicity, fatigue Premedicate with corticosteroid, antipyretic, and antihistamine Monitor for at least 1 hour post-infusion for infusionrelated reactions Leukemia, lymphoma Binds to CD20, eventually leadIV; administer for 6 cycles, dose Hypophosphatemia, hypocalcemia, hyperkalemia, hyponatreing to cell death varies on day and cycle mia, hypoalbuminemia, Premedicate with acetaminoleukopenia, elevated LFTs, phen, dexamethasone, and an anemia, infection, decreased antihistamine for Cycle 1 creatinine clearance, cough, Monitor CBC and electrolytes infusion-related reactions Patients should avoid live vaccines and should monitor for kidney or liver dysfunction Weakness, myalgias, neutropeBreast cancer Targets HER2 protein on breast IV; administer initial dose of nia, anemia, diarrhea, nausea, cancer cells 840 mg over 60 minutes, then vomiting, alopecia, rash, 420 mg every 3 weeks fatigue, headache, left ventricMonitor LVEF for cardiac failular cardiac dysfunction, infuure/dysfunction symptoms sion-related reactions Decreased LVEF, pain, chills, IV; administer initial dose of Breast cancer, gastric cancer Targets HER2 protein and supheadache, diarrhea, nausea, 2 8 mg/kg, dependent upon presses cancer cell growth and vomiting, abdominal pain, cancer type proliferation weakness, cough, dyspnea, Monitor LVEF and for cardiac fever, infusion-related failure/dysfunction symptoms reactions Hematologic toxicity, fatigue, Relapsed or refractory follicular Binds to the CD20 antigen found IV; administered on a specific nasopharyngitis, nausea, regiment that includes “preon B cells, allowing radiation B-cell or low-grade NHL, follicabdominal pain, asthenia, targeting” of the tissues with from the attached isotope to ular lymphoma in patients cough, diarrhea, fever, secondthe mAb rituximab first destroy the cancer cells and who achieved a complete or ary leukemias, severe infuMonitor CBC weekly for up to those in the immediate partial response to first-line sion-related reactions, severe 3 months after administration proximity chemotherapy cutaneous and mucocutaneous Instruct patients to use effecreactions (erythema multitive contraception methods forme, Stevens-Johnson synduring treatment and for 12 drome, toxic epidermal months post-administration necrolysis, dermatitis) Instruct patients not to receive live vaccines renal cell cancer, primary peritoneal, fallopian tube)
Elotuzumab Classification: Humanized Type: Unconjugated
Gemtuzumab ozogamicin Classification: Humanized Type: Conjugated
Inotuzumab ozogamicin Classification: Humanized Type: Conjugated
Oblinutuzumab Classification: Humanized Type: Unconjugated
Pertuzumab Classification: Humanized Type: Unconjugated
Trastuzumab Classification: Humanized Type: Unconjugated
Y-ibrutumomab tiuxetan Classification: Murine Type: Radioimmunotherapy/ conjugated
Abbreviations: ALL, acute lymphoblastic leukemia; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CLL, chronic lymphocytic leukemia; CBC, complete blood count; EGFR, epidermal growth factor receptor; GI, gastrointestinal; IV, intravenous; LFT, liver function test; LVEF, left ventricular ejection fraction; NHL, non-Hodgkin lymphoma; SC, subcutaneous Data from AstraZeneca,11 National Cancer Institute,12 and Olsen et al.13
target in hopes of discovering the “magic bullet” that will eliminate cancer altogether. While the associated side effects can be significantly less toxic than that of traditional chemotherapy, these agents can still pose a significant risk to patients. Therefore, nurses play a vital role in communicating with the other care team members and providing adequate patient education to ensure patient safety.
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3. Kaunitz J. Development of monoclonal antibodies: the dawn of mAb rule. Dig Dis Sci. 2017;62:831–832. 4. Liu J. The history of monoclonal antibody development progress, remaining challenges and future innovations. Ann Med Sci. 2014;3:113–116. 5. Shepard HM, Phillips GL, Thanos CD, Feldmann MD. Developments in therapy with monoclonal antibodies and related proteins. Clin Med (Lond). 2017;17:220–232. 6. Buss NA, Henderson SJ, McFarlane M, Shenton JM, de Haan L. Monoclonal antibody therapeutics: History and future. Curr Opin Pharmacol. 2012;12:615–622. 7. Garcia Merino A. Monoclonal antibodies basic features. Neurologia. 2010;26:301–306. 8. Modjtahedi H, Essapen S. Therapeutic application of monoclonal antibodies in cancer: advances and challenges. Br Med Bull. 2012;104:41–59. 9. American Cancer Society. Monoclonal antibodies to treat cancer. 2016. Available at: https://www.cancer.org/treatment/treatments-and-side-effects/treatmenttypes/immunotherapy/monoclonal-antibodies.html. (Accessed 03/27/19). 10. Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012;12: 278–287.
11. Guan M, Zhou Y, Sun J, Chen S. Adverse events of monoclonal antibodies used for cancer therapy. BioMed Res Int. 2015;15:1–13. 12. AstraZeneca. Lumoxiti for healthcare professionals. 2019. Available at: https:// www.lumoxitihcp.com/. (Accessed 03/27/2019). 13. National Cancer Institute. Brentuximab vedotin approved for two rare lymphomas. 2017. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/ 2017/brentuximab-fda-rare-lymphomas. (Accessed 03/27/2019). 14. Olsen M, LeFebvre K, Brassil K. Chemotherapy and Immunotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA; Oncology Nursing Society. 15. Wiley K, LeFebvre K, Wall L, et al. Immunotherapy administration: Oncology Nursing Society recommendations. Clin J Oncol Nurs. 2017;21:5–7. 16. Pirschel C. Monoclonal antibodies should have 2-RN verification. ONS Voice. 2017;32:39. 17. Bohnenkamp S. Immuno-oncology: another option for treatment of cancer. MedSurg Nurs. 2018;27:336–339.