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Review

Immune- and Non-Immune-Mediated Adverse Effects of Monoclonal Antibody Therapy: A Survey of 110 Approved Antibodies

by
Brian A. Baldo
1,2,†
1
Kolling Institute of Medical Research, Royal North Shore Hospital of Sydney, Sydney, NSW 2065, Australia
2
Department of Medicine, University of Sydney, Sydney, NSW 2065, Australia
†
The author is retired. His positions and affiliations are those prior to his retirement.
Antibodies 2022, 11(1), 17; https://doi.org/10.3390/antib11010017
Submission received: 20 December 2021 / Revised: 8 February 2022 / Accepted: 22 February 2022 / Published: 25 February 2022
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Abstract

:
Identification of new disease-associated biomarkers; specific targeting of such markers by monoclonal antibodies (mAbs); and application of advances in recombinant technology, including the production of humanized and fully human antibodies, has enabled many improved treatment outcomes and successful new biological treatments of some diseases previously neglected or with poor prognoses. Of the 110 mAbs preparations currently approved by the FDA and/or EMA, 46 (including 13 antibody–drug conjugates) recognizing 29 different targets are indicated for the treatment of cancers, and 66, recognizing 48 different targets, are indicated for non-cancer disorders. Despite their specific targeting with the expected accompanying reduced collateral damage for normal healthy non-involved cells, mAbs, may cause types I (anaphylaxis, urticaria), II (e.g., hemolytic anemia, possibly early-onset neutropenia), III (serum sickness, pneumonitis), and IV (Stevens–Johnson syndrome, toxic epidermal necrolysis) hypersensitivities as well as other cutaneous, pulmonary, cardiac, and liver adverse events. MAbs can provoke severe infusion reactions that resemble anaphylaxis and induce a number of systemic, potentially life-threatening syndromes with low frequency. A common feature of most of these syndromes is the release of a cascade of cytokines associated with inflammatory and immunological processes. Epidermal growth factor receptor-targeted antibodies may provoke papulopustular and mucocutaneous eruptions that are not immune-mediated.

1. Introduction

In the last decade, along with the continuing development of the disciplines of ge-nomics, proteomics, and bioinformatics and the application of molecular biological approaches to elucidate the functions of single genes, advances have led to insights into the complexities and multifaceted nature of diseases such as cancer, immune and inflammatory-based diseases, metabolic disorders, neurological diseases, transplantation, and some poorly understood dermatologic toxicities [1,2,3,4,5,6]. Specific, targeted approaches now employed in many monoclonal antibody (mAb), fusion protein, and cytokine therapies have been enabled by advances in recombinant DNA technology, the preparation of human recombinant antibody libraries, today’s sequencing methods, parallel proteome analyses employing techniques such as mass spectroscopy, and single B cell technologies [5,6,7]. The U.S. Food and Drug Authority (FDA) Office of Orphan Products Development and its European equivalent have provided extra stimulus for the development of therapies for “orphan diseases”, that is, diseases with less than 200,000 patients [8]. This stimulus has led to the introduction of effective approved mAb therapies for some diseases with low patient numbers previously neglected because of the lack of pathogenetic and pathophysiological insights into rare disorders where the potentially small market often precluded investigations [9].
Expanding understanding of ligand–receptor interactions; downstream signaling; and the delineation of immunological and inflammatory interplay between cells, anti-bodies, cytokines, and chemokines has contributed to the identification and selection of new disease biomarker targets. This, in turn, has created the opportunity to specifically target implicated cells, largely without inflicting collateral damage on normal healthy non-involved cells [10]. However, in addition to true hypersensitivities and infusion reactions, the expanding list of disease indications has sometimes brought with it adverse effects on the lungs, heart, liver, immune system, and skin in a variety of poorly, or partially understood, complex adverse responses [3]. A number of systemic potentially life-threatening syndromes most associated with inflammatory and immunological processes, often with cytokine involvement, also occur with low frequency during or following mAb therapy [3].
Although there are many hundreds of mAbs intended for therapeutic use at various stages of development, here we restrict examination to the 110 antibodies currently registered and approved by the U.S. Food and Drug Administration (FDA) and/or European Medicines Agency (EMA). Note, however, that some of these mAbs were first approved by other agencies while some others are already approved by other agencies but not the FDA and EMA.
Here, focus is directed to the classification of the 110 mAbs, their antibody targets, approved disease indications, and the adverse events associated with their use.

2. Evolution of Monoclonal Antibodies to Avoid Immunogenicity

Early realization that the murine composition of the first mAbs provoked a high incidence of adverse events including anaphylaxis and cytokine release syndrome, together with their poor pharmacokinetics, led to an ongoing iterative program to reduce, and ultimately eliminate, these undesirable features [3,11,12]. The mouse mAbs ibritumomab tiuxetan and tositumomab were soon followed by chimeric antibodies such as abciximab, cetuximab, infliximab, and others in which variable (antigen binding) regions were inserted into the constant regions of human immunoglobulins (Figure 1). Occasional serious hypersensitivities occurring after chimeric antibody infusions led to production of so-called humanized antibodies in which only approx. 5–10% of murine proteins remained after substituting mouse complementarity-determining (hypervariable) regions in place of human sequences (Figure 1). It became apparent, however, that even single amino acid changes could result in changes in antibody binding and affinity, and posttranslational glycosylation sometimes produced reductions in specificity, potency, and solubility without a reduction in immunogenicity. Development of the powerful technologies of phage display and transgenic mice finally enabled the production of fully human mAbs; however, immunogenicty can still be an occasional problem [3] due to the presence of anti-idiotype antibodies and antibodies to some mAbs (anti-glycan, anti-hinge, anti-allotype, rheumatoid factors) occurring in normal sera and sera of pretreated patients.

3. Monoclonal Antibody Targets and Indications

Of the 110 currently approved and registered mAbs (Table 1 and Table 2), two, alemtuzumab and denosumab, are each marketed as two separately approved products with different indications for each. Alemtuzumab, under trade names of Lemtrada® and Campath®/MabCampath® [13,14], is indicated for multiple sclerosis and B cell chronic lymphocytic leukemia, respectively, while denosumab as Prolia® is indicated for bone loss and, as Xgeva®, for bone metastases from solid tumors and giant cell tumor of bone [15,16]. Therefore, while the total number of approved mAbs shown in Table 1 and Table 2 is 112 (66 for non-cancer and 46 for cancer therapies), alemtuzumab and denosumab each appear in both lists under different trade names.
With the steady increase in the identification and association of biomarker targets [3,17] for an expanding range of diseases, a total of 77 different targets have thus far been utilized in the preparation of the 110 currently approved mAbs with some targets complementary to more than one mAb (Table 3). In particular, there are 29 targets for the 46 different mAb cancer therapies (Table 2) and a collective of 48 targets for a diverse range of 66 mAbs for non-cancer disorders, including 27 inflammatory and/or immune disorders and 39 other diseases/applications (Table 1). For the mAbs used for non-cancer therapies, 14 different targets have been employed two or more times (Table 3). For example, TNF as target has been utilized for four mAbs—adalimumab, certolizumab pegol, golimumab, and infliximab—each used in the treatments of inflammatory diseases including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, and Crohn’s disease. IL-6R serves as target for three different mAbs—sarilumab and tocilizumab, each used to treat rheumatoid arthritis, and satralizumab-mwge, indicated for a quite different condition, neuromyelitis optica spectrum disorder (Table 1 and Table 3). For the treatment of cancers, eight different targets are utilized for more than one mAb. The targets HER2, EGFR, programmed cell death protein 1 PD-1, and its ligand PD-L1 have been used as complementary targets for, respectively, five, four, three, and four different mAbs (Table 2 and Table 3).

4. Adverse Events to Monoclonal Antibody Therapy

Despite their target specificity, their low tendency for drug–drug interactions, and their generally better patient tolerance than small molecule drugs, mAbs are, unsurprisingly, not free of adverse effects, which may manifest as immune, non-immune, or direct cytotoxic reactions. Table 4 and Table 5 summarize adverse events associated with mAbs used for non-cancer and cancer therapies, respectively. For all mAbs, there is the possibility of injection site reactions, infusion reactions, hypersensitivity, and immunogenicity, although these effects are more likely with some mAbs than others. Many of the approved mAbs are subject to warnings for “hypersensitivity”, often without further qualification, which is generally unhelpful given the loose usage of this term and the fact that it often has a different meaning to clinicians and investigators in different branches of medicine [18,19]. Immunogenicity is always a concern even with fully human antibodies since anti-idiotype responses can occur [3,20].
Adverse events, divided into immune, that is true hypersensitivities, and non-immune, are herein considered.

4.1. Immune-Mediated Adverse Responses (Hypersensitivities) to Approved Monoclonal Antibodies

Collectively, patient responses to mAbs cover the full range of hypersensitivities from types I to IV (Box 1) [19] with the type I IgE-antibody-mediated hypersensitivity responses—anaphylaxis; urticaria (e.g., to ofatumumab and alemtuzumab); and, rarely, angioedema (e.g., with trastuzumab) occasionally seen. Chimeric mAbs with mouse and/or rat sequences (abciximab, basiliximab, blinatumomab, brentuximab vedotin, catumaxomab, cetuximab, dinutuximab, infliximab, obiltoxaximab, rituximab, and siltuximab) are considered to be the highest risk for type I reactions. Overall, however, reports of type I hypersensitivities are relatively rare, and perhaps less than expected, with only two FDA black box warnings issued thus far (for the humanized mAbs reslizumab and obiltoxaximab) and two FDA warning/precaution for palivizumab and brentuximab vedotin. Table 6 lists 19 mAbs with warnings for, and reports of, anaphylaxis, with 5 employed in cancer therapy (Table 5) and 14 for other disorders (Table 4). Severe infusion reactions that occur with some mAbs and which show some similar symptoms to anaphylaxis (see Section 4.2) can sometimes make distinguishing the two difficult and lead to doubts about the true incidence of anaphylaxis.
Box 1. Hypersensitivity reactions, known and some suspected, to approved monoclonal antibodies used for therapy.
  • TypeI hypersensitivity: Warnings for, and reports of, anaphylaxis account for ≈18% of mAbs, 14 used for non-cancer indications and 5 for cancer indications. Reslizumab and obiltoxaximab are covered by a black box warning for anaphylaxis. Urticaria occurs more often with the non-cancer mAbs.
  • Serious infusion reactions with signs and symptoms resembling, and sometimes confused with anaphylaxis, occur with some mAbs, for example, alemtuzumab, cetuximab, dinutuximab, ibritumomab tiuxetan, naxitamab-gqgk, panitumumab, rituximab, trastazumab, and vedolizumab. Cytokine release appears to be involved.
  • There is as yet no good evidence that many cytopenias are type II hypersensitivities, but these may occur with, for example, abciximab, alemtuzumab for multiple sclerosis and rituximab. Autoimmune hemolytic anemia may be induced by alemtuzumab and rituximab and rituximab-induced early- and late-onset neutropenia may be immune-mediated.
  • Type III hypersensitivities, serum sickness-like reactions, cutaneous vasculitis, and hypersensitivity pneumonitis (may be a combined type III and IV hypersensitivity) occur with, for example, infliximab, adalimumab, and alirocumab. Checkpoint inhibitors including ipilimumab, nivolumab, and avelumab (Table 5) may also induce hypersensitivity pneumonitis. Chimeric mAbs (e.g., rituximab) and the humanized mAb omalizumab may cause a serum sickness-like reaction.
  • Precise mechanisms for immune-mediated colitis, hepatitis, nephritis, hypothyroidism, and endocrinopathies induced by mAbs targeted to PD-1 and PD-L1 checkpoint inhibitors are not yet established.
  • Type IV hypersensitivities: Rare Stevens–Johnson syndrome reactions have been reported to adalimumab, brentuximab vedotin, infliximab, and rituximab; toxic epidermal necrolysis has been induced by ibritumomab tiuxetan and rituximab. Adalimumab, ibritumomab tiuxetan, infliximab, and naxitamab-gqgk have been implicated in cases of erythema multiforme (EM). Paraneoplastic pemphigus, lichenoid dermatitis, and vesiculobullous dermatitis have occurred after rituximab. Dermatitis may occur after some mAbs, e.g., bevacizumab, catumaxomab, denosumab, and panitumumab. Immune-mediated cutaneous reactions induced by, e.g., cemiplimab-rwlc and durvalumab may be type IV hypersensitivities but mechanisms are not yet unequivocally established. Skin manifestations of rash and pruritus, often seen after many mAbs (Table 4 and Table 5), are generally not true hypersensitivity reactions.
There are a number of reports of mAb-induced cytopenias suggesting an underlying immune mechanism [19], but because of the lack of proper investigations, there are few convincing reports of the involvement of mAbs in type II hypersensitivity responses (Box 1). Thrombocytopenia after abciximab treatment [24,25] and cases of alemtuzumab-induced immune thrombocytopenia [26,27], neutropenia [27], autoimmune hemolytic anemia [28,29], and pure red cell aplasia [27] provide perhaps the best examples of immune-mediated true hypersensitivity responses. Apart from abciximab and alemtuzumab, rituximab has been implicated in thrombocytopenia [30], anemia [30], severe autoimmune hemolytic anemia [31], and early-onset and late-onset forms of neutropenia [30,32,33]. Although early- and late-onset neutropenia are well-known side effects of rituximab, the mechanisms have yet to be firmly established. Both forms are suspected examples of a mAb-induced type II hypersensitivity, although late-onset neutropenia may involve autoantibodies and appears to be due to a different mechanism than the early-onset form. Involvement of trastuzumab in severe thrombocytopenia has been reported [34]. See also the section on cytopenias below and Table 6.
Hypersensitivity (cutaneous) vasculitis (Figure 2), serum sickness, and hypersensitivity pneumonitis are examples of type III hypersensitivities induced by mAbs (Box 1, Table 5). Apart from the fully human mAbs adalimumab and alirocumab (the latter subject to a warning), for possible hypersensitivity vasculitis, again, the chimeric antibodies, such as rituximab and infliximab, are the biggest cause of reactions. For example, cutaneous vasculitis associated with infliximab in the treatment of rheumatoid arthritis is known [35], and there are a number of reports of rituximab-induced vasculitis [36,37] and serum sickness [38,39,40]. In fact, rituximab-induced serum sickness is said to occur in up to 20% of treated patients [41]. Checkpoint inhibitors ipilimumab, nivolumab, pembrolizumab, cemiplimab-rwlc, atezolizumab, avelumab, and durvalumab (Table 5) may cause hypersensitivity pneumonitis, generally thought to be a combined type III and IV hypersensitivity in a Th1/Th17 response [42,43,44]. As well as the adverse pulmonary reactions (Table 5 and Table 6), the checkpoint inhibitors may also provoke immune-mediated colitis, endocrinopathies, hepatitis, nephritis, and thyroiditis, reactions that might involve a type III hypersensitivity mechanism (Table 6).
Almost 40% of the 110 approved mAbs are associated with some sorts of adverse cutaneous effects, including type IV hypersensitivities [19] with rare cases of life-threatening cutaneous toxidermias (Table 4, Table 5 and Table 6, Box 1). Ibritumomab has an FDA boxed warning for severe cutaneous and mucocutaneous reactions, which includes Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), erythema multiforme (EM) (Figure 3), exfoliative dermatitis, and bullous dermatitis. Warnings and precautions apply to brentuximab vedotin for SJS; rituximab has been involved in cases of SJS, TEN, paraneoplastic pemphigus, lichenoid dermatitis, and vesiculobullous dermatitis; and EM has occurred with naxitamab-gqgk therapy. EM, SJS, and psoriasis have been reported for adalimumab. EGFR-targeted mAbs are known for so-called dermatologic acneiform toxicities that are not immune-mediated (see below, Section 4.2, Cutaneous reactions).

4.2. Non-Immune-Mediated Adverse Responses to Approved Monoclonal Antibodies

As mentioned above, despite the specific targeting of mAbs to a particular disease-/disorder-associated tissue(s), the range and number of adverse events during or following therapy can sometimes be large and diverse. As summarized and discussed in Table 4, Table 5 and Table 6 and Box 2, many of these events do not have an immune basis or such a basis has yet to be convincingly demonstrated, either because sufficient investigation has yet to be undertaken or because of the clinical and laboratory difficulties involved in defining a precise mechanism(s). The list of recorded mAb-induced non-immune events is extensive and includes injection site reactions, infusion reactions, cytopenias, lung and liver injuries, heart effects, dermatologic toxicities, embryo and fetal toxicities, and a number of potentially life-threatening syndromes occurring with low frequency (Table 6, Box 2). It should be pointed out, however, that within some of these categories, it might be argued that there is, or may be, an immunological component with the involvement of cells and/or cytokines normally present in many inflammatory and immunological reactions.
Injection site reactions are very common, and when the preferred terms used in the Federal Adverse Event (FAERS) reporting system to describe such reactions are considered, namely, irritation, erythema, rash, bruising, swelling, induration, extravasation, reactions, pruritus, urticaria, hemorrhage, hematoma, and pain, it becomes apparent as to why such patient reactions are seen so regularly. In any injected population, it is to be expected that at least some individuals will respond with at least one of the above adverse effects. In the post-marketing period, the larger the population injected, the wider the collective list of adverse effects seen. The preferred terms listed are from the Medical Dictionary for Regulatory Activities (MedDRA; http://www.meddra.org/ accessed on 14 December 2021). Of the 66 approved mAbs for non-cancer therapy surveyed here, the FDA in its warnings, precautions, and lists of adverse reactions mentions injection site reactions as an adverse event for 24 (≈37%).
Box 2. Non-immune-mediated adverse events to monoclonal antibodies (mAbs).
  • Infusion reactions. Usually mild–moderate or controllable by premedication. Fatal reactions can occur. Reactions have been recorded for almost 50% of approved mAbs. FDA boxed warnings for infusion reactions apply to 8 mAbs used for cancer therapy and 1 mAb used for other therapies.
  • Cytopenia: Mechanisms of mAb-induced thrombocytopenia, neutropenia, lymphopenia, and hemolytic anemia are often not investigated/established. Cytopenia seen in more than 30% of the mAbs, especially those used in cancer therapy. Some may be immune-mediated.
  • mAb-induced lung disease: Pathogenesis and pathophysiology are generally not known. At least 21 mAbs implicated. Some reactions are known, or suspected, to be immune-mediated.
  • Cardiac events: Mechanisms mostly obscure. At least 20 mAbs implicated.
  • Liver events: At least 22 mAbs implicated. Immune-mediated hepatitis is seen but other mechanisms often not well understood.
  • Dermatologic toxicities: 39 (≈36%) of the mAbs elicited adverse cutaneous reactions of different severity from mild to severe. Rash and/or pruritus are common and were not included in the assessments. Apart from severe toxidermias (see text), papulopustular (acneiform) skin eruptions occur in response to EGFR-targeted antibodies, in particular, cetuximab, necitumumab, and panitumumab. Adverse reactions were seen in ≈29% of the non-cancer group and 50% of the mAbs used for cancer therapy.
  • Embryo-fetal toxicity is recognized for 27 (≈25%) of the mAbs, including eight antibody–drug conjugates.
  • Cytokine release syndrome (CRS): The distinguishing features between CRS and infusion reactions are often not clear. mAbs implicated include blinatumomab and catumaxomab.
  • Tumor lysis syndrome (TLS): Anti-cancer mAbs may destroy large numbers of cells in a short period of time. Seen with brentuximab vedotin, blinatumomab, rituximab, and polatuzumab vedotin-piiq.
  • Progressive multifocal leukoencephalopathy (PML): Rare but occasionally seen after mAbs directed to B cells, e.g., brentuximab vedotin, rituximab, obinutuzumab, vedolizumab, polatuzumab vedotin-piiq, and natalizumab.
  • Other syndromes of poorly understood pathogenesis: Reversible posterior leukoencephalopathy syndrome (RPLS) 1 (cases reported after, e.g., bevacizumb and ramucirumab); immune reconstitution inflammatory syndrome (IRIS) (natalizumab); systemic inflammatory response syndrome (SIRS) (catumaxomab, eculizumab); capillary leak syndrome (CLS) (bevacizumab, dinutuximab); macrophage activation syndrome (MAS) (canakinumab).
1 Also known as posterior reversible encephalopathy syndrome (PRES)
Infusion reactions [3,19] to mAbs are common, usually with mild to moderate ‘flu’-like symptoms, but serious, potentially fatal reactions can occur. Table 6 shows that infusion reactions are known for 53 of the 110 approved mAbs (Table 4 and Table 5). Reactions may resemble anaphylaxis, and hypotension, cardiac arrest, urticaria, rash and pruritus may occur, usually after the first or second infusion, but IgE antibody reactions generally have a faster onset (often within minutes) and effects are more severe. The cytokines tumor necrosis factor (TNF) and IL-6, as well as high counts of circulating lymphocytes (e.g., >50 × 109/L) are thought to be involved [45]. The highest incidence of reactions occurs with human–rodent chimeric antibodies, e.g., rituximab and infliximab, and some humanized mAbs such as alemtuzumab, ocrelizumab, and trastuzumab. Table 6 lists the 53 mAbs shown to provoke infusion reactions. Rituximab and trastuzumab show the highest incidence of reactions with incidences for first infusion reactions of ≈77% and ≈40%, respectively. Premedication may be necessary in order to avoid or lessen reactions, for example, as sometimes found necessary with elotuzumab infused for multiple myeloma [46]. Overall, mAbs involved show a two to one infusion reaction ratio of mAbs for cancer compared to those for other indications. Eight mAbs for cancer indications carry a black box warning for infusion reactions, while 22 are subject to a warnings and precautions notice. The corresponding warnings for mAbs used for non-cancer therapies are one and nine, respectively.
Cytopenias commonly occur during and/or following mAb therapy, especially as a result of anti-cancer therapies. Of 34 mAbs implicated in the induction of cytopenias, 24 (≈71%) are anti-cancer agents and 10 (≈29%) relate to other indications (Table 4, Table 5 and Table 6). FDA boxed warnings have been issued for three mAbs, namely, for sacituzumab govetican-hziy-induced severe neutropenia and for cytopenia following ibritumomab tiuxetan and alemtuzumab, while FDA general warnings and precautions apply to 21 other mAbs listed in Table 7. In addition, other warnings of adverse events apply to brodalumab for neutropenia; to tocilizumab for neutropenia and thrombocytopenia; and to different cytopenias, namely, lymphocytopenia, for a high proportion of anti-neoplastic mAbs (Table 4 and Table 5). Note that because mechanisms of mAb-induced thrombocytopenia, neutropenia, lymphocytopenia, anemia, and what is often simply termed ‘cytopenia’ are often not investigated, some events may, in fact, be immune-mediated.
Mab-induced pulmonary adverse events comprise a heterogeneous group of disorders, many of which remain poorly understood mechanistically. Of the 21 mAbs (counting alemtuzumab as Lemtrada® and Campath® as one mAb) listed in Table 6 and Box 3 (see also Table 4 and Table 5), immune-mediated or hypersensitivity pneumonitis is recognized as an important adverse event for an increasing number of mAbs, particularly checkpoint inhibitors [42,43,44,47]. This condition is now considered to be a combined type III and IV hypersensitivity in a Th1/Th17 response. Pneumonitis associated with checkpoint inhibitors is a rare, potentially fatal immune disease with an incidence of 2–5% [48]. Interestingly, the incidence is higher in non-small cell lung cancer than in melanoma [49]. For rituximab, while early-onset organizing pneumonia may be a hypersensitivity reaction, its prognosis is poorer than the late-onset form [50], which may be either a toxicity or due to immune restoration. Acute respiratory distress syndrome (ARDS) [51], seen for example with rituximab, trastuzumab, and ado-trastuzumab, may result from the release of pro-inflammatory cytokines such as IL-1β, TNF-α, IL-6, and IL-8, which are elevated both in bronchoalveolar lavage fluid and circulating plasma in ARDS patients [52]. Rituximab, alemtuzumab, trastuzumab, and panitumumab are responsible for the most severe and widest range of adverse lung events (Box 3).
Adverse cardiac events have occurred with at least 20 of the 110 approved mAbs (Table 4, Table 5 and Table 6 and Table 8) in a range of effects, including cardiomyopathy, myocardial infarction, cardiac arrhythmias, cardiopulmonary arrest, congestive heart failure, left ventricular dysfunction (LVD), decreased left ventricular ejection fraction (LVED), and QT interval prolongation (Table 8). FDA black box warnings apply to necitumumab for cardiopulmonary arrest; romosozumab-aqqg for the risk of myocardial infarction, cardiac events, stroke, and cardiovascular death; aldo-trastuzumab emtansine for cardiac toxicity; margetuximab-cmkb for LVD; and pertuzumab and trastuzumab, each for cardiomyopathy. Patients given mAbs targeted to HER2, namely, trastuzumab, ado-trastuzumab emtansine, and pertuzumab, show an increased risk of decreased LVED, especially if also given anthracyclines. Trastuzumab increases the risk of myocardial infarction 4–6 times, and again, the risk is highest when anthracyclines are also administered. Fam-trastuzumab deruxtecan-nxki carries a warning for LVD. Kounis and coworkers [53] believe that it is likely that many of the cardiac toxicities associated with mAbs used in cancer therapy share the same pathophysiology with Kounis syndrome. Suggested possible mAb involvements include -ximabs (e.g., rituximab, cetuximab, brentuximab); -zumabs (alemtuzumab, bevacizumab, trastuzumab, pertuzumab); -umabs (ipilimumab, panitumumab); and -omabs (catumaxomab, ibritumomab).
Box 3. Pulmonary adverse events caused by approved monoclonal antibodies.
  • Mouse antibodies
    ߋ
    Ibrutumomab tiuxetan: hypersensitivity bronchospasm
  • Human-mouse chimeric antibodies
    ߋ
    Cetuximab: interstitial pneumonitis
    ߋ
    Infliximab: interstitial lung disease
    ߋ
    Rituximab: ARDS, BOOP, bronchospasm, diffuse alveolar hemorrhage, immune-mediated (hypersensitivity) pneumonitis
  • Humanised antibodies
    ߋ
    Ado-trastuzumab: interstitial lung disease, pneumonitis, ARDS, dyspnea, pulmonary infiltrates, radiation pneumonitis
    ߋ
    Alemtuzumab: pneumonitis, bronchospasm, diffuse alveolar hemorrhage, pulmonary infection
    ߋ
    Amivantamab-vmjw: interstitial lung disease, pneumonitis
    ߋ
    Atezolizumab: immune-mediated pneumonitis, dyspnea
    ߋ
    Bevacizumab: anaphylaxis/bronchospasm, pulmonary hemorrhage from tumor site
    ߋ
    Dostarlimab-gxly: immune-mediated pneumonitis
    ߋ
    Fam-trastuzumab deruxtecan-nxki: interstitial lung disease, pneumonitis
    ߋ
    Pembrolizumab: immune-mediated pneumonitis, dyspnea
    ߋ
    Trastuzumab: ARDS, BOOP, dyspnea, interstitial pneumonitis, pleural effusions, pulmonary infiltrates/fibrosis/edema
  • Fully human antibodies
    ߋ
    Adalimumab: interstitial lung disease
    ߋ
    Avelumab: immune-mediated pneumonitis
    ߋ
    Cemiplimab-rwlc: immune-mediated pneumonitis
    ߋ
    Durvalumab: immune-mediated pneumonitis, dyspnea
    ߋ
    Golimumab: interstitial lung disease
    ߋ
    Ipilimumab: immune-mediated pneumonitis
    ߋ
    Nivolumab: immune-mediated pneumonitis, dyspnea
    ߋ
    Panitumumab: interstitial lung disease, lung infiltrates, pneumonitis, pulmonary fibrosis
    ߋ
    Tisotumab vedotin-tftv: pneumonitis
ARDS—acute respiratory distress syndrome; BOOP—bronchiolitis obliterans organizing pneumonia; ‘pneumonitis’ is used when the mechanism remains uncertain.
As occurs with mAb-induced pulmonary adverse events, checkpoint inhibitors, both PD-L1- and PD-l-targeted mAbs, may elicit immune adverse reactions in the liver in the form of immune-mediated hepatitis. Another immune-based adverse effect may occur with the CD25 (IL-2R α-chain)-targeted mAb daclizumab, which is subject to an FDA box warning for hepatic injury including via an autoimmune mechanism. Other mAb-provoked adverse liver injuries include direct toxicities and reactivation of hepatitis (Table 4, Table 5 and Table 6 and Table 9). FDA warnings and precautions for non-immune mAb-induced liver injury apply to adalimumab, certolizumab pegol, evolocumab, golimumab, infliximab, natalizumab, vedolizumab, brentuximab vedotin, catumaxomab, cemiplimab-rwlc, elotuzumab, ofatumumab, polatuzumab vedotin-piiq, and rituximab. Four mAbs are subject to boxed warnings, gemtuzumab ozogamicin and inotuzumab ozogamicin for hepatotoxicity, including severe or fatal hepatic veno-occlusive disease; ado-trastuzumab emtansine for hepatotoxicity; and obinutuzumab for hepatitis B reactivation (Table 9). Three of these four mAbs are antibody–drug conjugates, suggesting involvement of the attached toxin in the severe hepatotoxicities. A warning applies to satralizumab-mwge for elevated liver enzymes ALT and AST.
Cutaneous reactions have been associated with at least 39 of the 110 different mAbs (≈36%; counting alemtuzumab and denosumab each only once) (Table 6). As discussed above, some of these reactions are true type IV hypersensitivities, and there are a few recorded examples of type I reactions such as urticaria (e.g., alirocumab), but mechanisms remain to be established for many of the other adverse events (Table 4 and Table 5, Box 2). FDA warnings and precautions for dermatologic toxicity/reactions have been issued for cemiplimab-rwlc, cetuximab, denosumab, dostarlimab-gxly, durvalumab, enfortumab vedotin-ejfv, and mogamulizumab-kpkc. It is not clear whether or not at least some of the skin reactions following checkpoint inhibitors (cemiplimab-rwlc, dostarlimab-gxly, durvalumab) are immune-mediated. Skin reactions to loncastumab tesirine-lpyl may also demonstrate photosensitivity. Antibodies targeted to EGFR, namely, amivantamab-vmjw, cetuximab, necitumumab, and panitumumab, are known to produce, and are subject to, FDA warnings for papulopustular (acneiform) skin eruptions (Figure 4) [54] and mucocutaneous reactions (mucositis, xerosis, paronychia, fissures, palmar-plantar rash, skin hyperpigmentation, and others), both of which are not immune-mediated. In addition, panitumumab carries an FDA black box warning for dermatologic toxicity and has been implicated in cases of erythema, exfoliation, paronychia, skin fissures, photosensitivity, xerosis, and pruritus.

4.3. Rare Syndromes Associated with Monoclonal Antibody Therapy

Some rare, potentially life-threatening syndromes (Box 4) may occur with low frequency following the administration of some mAbs. Cytokine release syndrome (CRS) [55] shows similarities to severe infusion reactions in that both are related to a high lymphocyte count; counts greater than 50 × 109/L are associated with CRS and the release of TNF and IL-6. Symptoms include fever, chills, hypotension, nausea, vomiting, dyspnea, and an increase in liver enzymes. Rituximab is a well-known cause of CRS; other implicated mAbs are alemtuzumab, blinatumomab, and catumaxomab. Hemophagocytic lymphohistiocytosis (HLH) [56] is a rare, highly inflammatory disorder resembling cytokine storm involving proliferation of activated T cells and macrophages with the release of large amounts of cytokines, particularly IFN gamma, TNF, and GM-CSF. IL-1 and IL-6 released from activated macrophages are responsible for the inflammatory response, tissue damage, and symptoms of HLH. Two forms of HLH are known, primary, or familial, HLH and secondary, or acquired, HLH that occurs after malignancy, infection, or immunodeficiency. Blinatumomab is well known to be a rare cause and, more recently, immune checkpoint inhibitors avelumab, ipilimumab, and nivolumab have been rarely implicated. In the immune reconstitution inflammatory syndrome (IRIS) [57], also called immune recovery syndrome, restoration of immunity is, paradoxically, accompanied by deterioration of a known or new condition. Examples of the syndrome are seen in AIDS and tuberculosis. The pathogenesis of the condition is poorly understood. MAbs implicated in IRIS are adalimumab, ibalizumab-uiyk, infliximab, and natalizumab. Macrophage activation syndrome (MAS) [58] resembles HLH, but the name is traditionally reserved for the HLH-like inflammatory reaction seen in at least 10% of patients with rheumatologic diseases, in particular systemic juvenile idiopathic arthritis (SJIA). MAS, which can be rapidly fatal, is mediated by an uncontrolled proliferation of T cells and macrophages exhibiting hemophagocytic activity [59]. MAbs known to precipitate the syndrome include alemtuzumab, canakinumab, and tocilizumab. Progressive multifocal leukoencephalopathy (PML) [60] is a rare, usually fatal demyelinating disease characterized by inflammation and progressive brain damage. It is caused by infection with the normally harmless JC virus that becomes lethally active in immunosuppressed patients, in some autoimmune diseases, and in patients receiving chemotherapy, including some biologics. MAbs involved include belimumab, brentuximab vedotin, infliximab, eculizumab, natalizumab, ofatumumab, polatuzumab vedotin-piiq, rituximab, and vedolizumab. In reversible posterior encephalopathy syndrome (RPLS), also called posterior reversible encephalopathy syndrome (PRES [61]), edematous changes occur in the brain perhaps as a result of systemic hypertension leading to hypoxia and vasogenic edema. However, some cases of RPLS appear to occur in the absence of hypertension and others in the absence of inflammation. MAbs associated with RPLS include bevacizumab, certolizumab pegol, infliximab, dinutuximab, naxitamab-gqgk, ramucirumab, rituximab, and ustekinumab. Systemic capillary leak syndrome (SCLS) [62], also known simply as capillary leak syndrome, vascular leak syndrome, and Clarkson’s disease, has symptoms of body weight increase, malaise, weakness, pyrexia, myalgia, abdominal pain/vomiting, and diarrhea. An increase in vascular permeability and extravasation of fluids leads to peripheral and interstitial edema and, in severe form, pulmonary and cardiovascular failure. MAbs reported to be associated with CLS include alemtuzumab, basiliximab, bevacizumab, catumaxomab, dinutuximab, the immune checkpoint inhibitor nivolumab, and rituximab. Systemic inflammatory response syndrome (SIRS) [63], related to sepsis, can cause organ dysfunction and failure. It may be caused by infection or have a noninfectious basis such as trauma, pancreatitis, ischemia, anaphylaxis, or treatment with a biologic agent. The condition proceeds via activation of an inflammatory cascade of cytokines including TNF; IFN gamma; and IL-1, -6, and -8. SIRS has been reported following catumaxomab and eculizumab. Tumor lysis syndrome (TLS) [64] occurs most often in patients with leukemia and high-grade lymphomas where there are large numbers of cancer cells. Death of the cells results in marked ionic imbalance due to hypercalcemia, hyperkalemia, hyperphosphatemia, and hyperuricemia. This can lead to renal failure, cardiac arrhythmias, seizures, and death. The mAbs most often associated with TLS are alemtuzumab, blinatumomab, brentuximab vedotin, ipilimumab, obinutuzumab, polatuzumab vedotin-piiq, and rituximab (Box 4).
Box 4. Monoclonal antibodies associated with rare syndromes.
  • Cytokine release syndrome (CRS)
    Alemtuzumab; blinatumomab; catumaxomab; rituximab
  • Hemophagocytic lymphohistiocytosis (HLH)
    Alemtuzumab; avelumab; blinatumomab; ipilimumab; nivolumab
  • Immune reconstitution inflammatory syndrome (IRIS)
    Adalimumab; ibalizumab-uiyk; infliximab; natalizumab
  • Macrophage activation syndrome (MAS)
    Alemtuzumab; canakinumab; tocilizumab
  • Progressive multifocal leukoencephalopathy (PML)
    Belimumab; brentuximab vedotin; infliximab; eculizumab; natalizumab; ocrelizumab; ofatumumab; polatuzumab vedotin-piiq; rituximab; vedolizumab
  • Reversible posterior encephalopathy syndrome (RPLS)
    Bevacizumab; certolizumab pegol; infliximab; dinutuximab; naxitamab-gqgk; ramucirumab; rituximab; ustekinumab
  • Systemic capillary leak syndrome (SCLS)
    Alemtuzumab; basiliximab; bevacizumab; catumaxomab; dinutuximab; nivolumab; rituximab
  • Systemic inflammatory response syndrome (SIRS)
    Catumaxomab; eculizumab
  • Tumor lysis syndrome (TLS)
    Alemtuzumab; blinatumomab; brentuximab vedotin; ipilimumab; obinutuzumab; polatuzumab vedotin-piiq; rituximab

5. Concluding Remarks

At the beginning of 2022, the catalog of mAbs approved for therapy by the FDA and/or EMA consisted of 66 approved for non-cancer indications and 46 for cancer therapy. Unsurprisingly because of their clinical success, the number of approved mAbs continues to expand, for example, in the 17 year period 1997–2013, 34 mAbs were approved, whereas in the 7 years of 2014–2020, the approved total was 61 (Figure 5) [65]. From 1997 until the present time (December 2021), 110 mAbs have received approval from the FDA and/or EMA (Figure 5). In 2021, 14 products were approved: aducanumab, amivantamab, anifrolumab, bimekizumab, casirivimab + imdevimab; dostarlimab-gxly, efgartigimod-alfa-fcab, evinacumab, loncastuximab teserine-lpyl, regdanvimab, sotrovimab, tezepelumab-ekko, tisotumab vedotin, and tralokinumab. Approved by the EMA, casirivimab + imdevimab, regdanvimab, and sotrovimab are the first three preparations for the treatment of COVID-19, each targeted to the spike protein receptor-binding domain of SARS-CoV-2 (Table 1). It is clear that from information on the numbers of mAbs already undergoing clinical assessment, as well as some already marketed for other indications with the view of repurposing for the treatment of COVID-19, further approvals of mAb preparations to treat this disease are imminent [65]. In late December 2021, efgartigimod-alfa-fcab indicated for myasthenia gravis and tezepelumab-ekko for severe asthma were approved by the FDA.
In the next few years, research and clinical progress in disease pathogenesis and the identification of new disease biomarker targets, together with ongoing orphan drug development programs, will continue an inevitable expansion of the list of approved mAbs. Aspects of this expansion of great interest include a growing list of new indications; further mechanistic insights into the interplay between antibodies, cells, cytokines, chemokines, receptor interactions and downstream signaling; the appearance of new, and some unexpected, adverse events; and progress in understanding and treating such events.

Funding

No funding was received in relation to the preparation of this work.

Institutional Review Board Statement

Not relevant to this review.

Informed Consent Statement

Not relevant to this review.

Data Availability Statement

Any relevant data is available from author on request.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Ossipow, V.; Fischer, N. (Eds.) Methods and protocols. In Method in Molecular Biology, 2nd ed.; Humana Press: New York, NY, USA, 2014; Volume 1131. [Google Scholar]
  2. Weiner, G.J. Building better monoclonal antibody-based therapeutics. Nat. Rev. Cancer 2015, 15, 361–370. [Google Scholar] [CrossRef] [Green Version]
  3. Baldo, B.A. Safety of Biologics Therapy: Monoclonal Antibodies, Cytokines, Fusion Proteins, Hormones, Enzymes, Coagulation Proteins, Vaccines, Botulinum Toxins; Springer Nature: Cham, Switzerland, 2016; pp. 1–215. [Google Scholar]
  4. Kumar, R.; Parray, H.A.; Shrivastava, T.; Sinha, S.; Luthra, K. Phage display antibody libraries: A robust approach for generation of recombinant human monoclonal antibodies. Int. J. Biol. Macromol. 2019, 135, 907–918. [Google Scholar] [CrossRef]
  5. Kaur, H.; Reusch, D. (Eds.) Monoclonal antibodies. In Physicochemical Analysis; Academic Press: London, UK, 2021. [Google Scholar]
  6. Pedrioli, A.; Oxenius, A. Single B cell technologies for monoclonal antibody discovery. Trends Immunol. 2021, 42, 1143–1158. [Google Scholar] [CrossRef]
  7. Mondon, P.; Dubreuil, O.; Bouayadi, K.; Kharrat, H. Human antibodies: A race to engineer and explore a larger diversity. Front. Biosci. 2008, 13, 1117–1129. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Food and Drug Administration. Rare Diseases: Common Issues in Drug Development Guidance for Industry. February 2019. Available online: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/rare-diseases-common-issues-drug-development-guidance-industry (accessed on 14 December 2021).
  9. Mulberg, A.E.; Bucci-Rechtweg, C.; Giuliano, J.; Jacoby, D.; Johnson, F.K.; Liu, Q.; Marsden, D.; McGoohan, S.; Nelson, R.; Patel, N.; et al. Regulatory strategies for rare diseases under current global regulatory statutes: A discussion with stakeholders. Orphanet J. Rare Dis. 2019, 14, 36. [Google Scholar] [CrossRef] [PubMed]
  10. Baldo, B.A.; Pagani, M. Adverse events to nontargeted and targeted chemotherapeutic agents. Immunol. Allergy Clin. N. Am. 2014, 34, 565–596. [Google Scholar] [CrossRef] [PubMed]
  11. Almagro, J.C.; Fransson, J. Humanization of antibodies. Front. Biosci. 2008, 13, 1619–1633. [Google Scholar] [CrossRef]
  12. Parray, H.A.; Shukla, S.; Samal, S.; Shrivastava, T.; Ahmed, S.; Sharma, C.; Kumar, R. Hybridoma technology a versatile method for isolation of monoclonal antibodies, its applicability across species, limitations, advancement and future perspectives. Int. Immunopharmacol. 2020, 85, 106639. [Google Scholar] [CrossRef]
  13. Lemtrada (alemtuzumab). Highlights of Prescribing Information. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103948s5158lbl.pdf (accessed on 14 December 2021).
  14. Campath (alemtuzumab). Highlights of Prescribing Information. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/103948s5070lbl.pdf (accessed on 14 December 2021).
  15. Prolia (denosumab). Highlights of Prescribing Information. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125320s205lbl.pdf (accessed on 14 December 2021).
  16. Xgeva (denosumab). Highlights of Prescribing Information. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125320s094lbl.pdf (accessed on 14 December 2021).
  17. Scott, A.M.; Wolchok, J.D.; Old, L.J. Antibody therapy of cancer. Nat. Rev. Cancer. 2012, 12, 278–287. [Google Scholar] [CrossRef]
  18. Baldo, B.A.; Pham, N.H. Drug Allergy: Clinical Aspects, Diagnosis, Mechanisms, Structure-Activity Relationships, 2nd ed.; Springer Nature: Cham, Switzerland, 2021; pp. 6–8. [Google Scholar]
  19. Baldo, B.A. Adverse events to monoclonal antibodies used for cancer therapy. Focus on hypersensitivity responses. OncoImmunology 2013, 2, e26333. [Google Scholar] [CrossRef] [Green Version]
  20. Stephens, S.; Emtage, S.; Vetterlein, O.; Chaplin, L.; Bebbington, C.; Nesbitt, A.; Sopwith, M.; Athwal, D.; Novak, C.; Bodmer, M. Comprehensive pharmacokinetics of a humanized antibody and analysis of residual anti-idiotypic responses. Immunology 1995, 85, 668–674. [Google Scholar]
  21. Howard, J.F.; Bril, V.; Vu, T.; Karam, C.; Peric, S.; Margania, T.; Murai, H.; Bilinska, M.; Shakarishvili, R.; Smilowski, M.; et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): A multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021, 20, 526–536. [Google Scholar] [CrossRef]
  22. Menzies-Gow, A.; Colice, G.; Griffiths, J.M.; Almqvist, G.; Ponnarambil, S.; Kaur, P.; Ruberto, G.; Bowen, K.; Hellqvist, Å.; Mo, M.; et al. NAVIGATOR: A phase 3 multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate Nthe efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma. Respir. Res. 2020, 13, 266. [Google Scholar] [CrossRef]
  23. Menzies-Gow, A.; Corren, J.; Bourdin, A.; Chupp, G.; Israel, E.; Wechsler, M.E.; Brightling, C.E.; Griffiths, J.M.; Hellqvist, Å.; Bowen, K.; et al. Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma. N. Engl. J. Med. 2021, 384, 1800–1809. [Google Scholar] [CrossRef] [PubMed]
  24. Curtis, B.R.; Swyers, J.; Divgi, A.; McFarland, J.G.; Aster, R.H. Thrombocytopenia after second exposure to abciximab-coated platelets. Blood 2002, 9, 2054–2059. [Google Scholar] [CrossRef] [PubMed]
  25. Sharma, S.; Bhambi, B.; Nyitray, W.; Sharma, G.; Shambaugh, S.; Antonescu, A.; Shukla, P.; Denny, E. Delayed profound thrombocytopenia presenting 7 days after use of abciximab (ReoPro). J. Cardiovasc. Pharmacol. Ther. 2002, 7, 21–24. [Google Scholar] [CrossRef]
  26. Cuker, A.; Bass, A.D.; Nadj, C.; Agius, M.A.; Steingo, B.; Selmaj, K.W.; Thoits, T.; Guerreiro, A.; Van Wijmeersch, B.; Ziemssen, T.; et al. Immune thrombocytopenia in alemtuzumab-treated MS patients: Incidence, detection, and management. Mult. Scler. J. 2020, 26, 48–56. [Google Scholar] [CrossRef] [Green Version]
  27. Aitken, L.; Patel, R.; D’Rozario, J.; Choi, P. Alemtuzumab induced red cell aplasia and other immune cytopenias—Not so ‘pure’. Immunotherapy 2021, 14, 95–99. [Google Scholar] [CrossRef]
  28. Reickmann, P.; Lenz, A.; Hoffmann, M. Fatal autoimmune hemolytic anemia associated with alemtuzumab in a MS patient with severe relapsing remitting disease course and prior immune therapies (P2.103). Neurology 2016, 86 (Suppl. 16), P2.103. [Google Scholar]
  29. Desai, P.A.; Romere, C.M.; Nguyen, L.; Saksena, A.; Abdullah, S.J.; Diaz, A.E. Severe Coombs positive autoimmune hemolytic anemia after alemtuzumab infusion for relapsing remitting multiple sclerosis. What can we learn? Blood 2018, 132 (Suppl. 1), 2331. [Google Scholar] [CrossRef]
  30. Cattaneo, C.; Spedini, P.; Casari, S.; Re, A.; Tucci, A.; Borlenghi, E.; Ungari, M.; Ruggeri, G.; Rossi, G. Delayed-onset peripheral blood cytopenia after rituximab: Frequency and risk factor assessment in a consecutive series of 77 treatments. Leuk. Lymphoma 2006, 47, 1013–1017. [Google Scholar] [CrossRef] [PubMed]
  31. Jourdan, E.; Topart, D.; Richard, B.; Jourdan, J.; Sotto, A. Severe autoimmune hemolytic anemia following rituximab therapy in a patient with a lymphoproliferative disorder. Leuk. Lymphoma 2003, 44, 889–890. [Google Scholar] [CrossRef] [PubMed]
  32. Dunleavy, K.; Tay, K.; Wilson, W.H. Rituximab-associated neutropenia. Semin. Hematol. 2010, 47, 180–186. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Weissmann-Brenner, A.; Brenner, B.; Belyaeva, I.; Lahav, M.; Rabizadeh, E. Rituximab-associated neutropenia: Description of three cases and an insight into the underlying pathogenesis. Med. Sci. Monit. 2011, 17, CS133–CS137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Mantzourani, M.; Gogas, H.; Katsandris, A.; Meletis, J. Severe thrombocytopenia related to trastuzumab infusion. Med. Sci. Monit. 2011, 17, CS85–CS87. [Google Scholar] [CrossRef] [Green Version]
  35. Anandacoomarasamy, A.; Kannangara, S.; Barnsley, L. Cutaneous vasculitis associated with infliximab in the treatment of rheumatoid arthritis. Intern. Med. J. 2005, 35, 638–640. [Google Scholar] [CrossRef]
  36. Kandula, P.; Kouides, P.A. Rituximab-induced leukocytoclastic vasculitis: A case report. Arch. Dermatol. 2006, 142, 243–253. [Google Scholar] [CrossRef]
  37. Kim, M.J.; Kim, H.O.; Kim, H.Y.; Park, Y.M. Rituximab-induced vasculitis: A case report and review of the medical published work. J. Dermatol. 2009, 36, 284–287. [Google Scholar] [CrossRef]
  38. D’Arcy, C.A.; Mannik, M. Serum sickness secondary to treatment with the murine-human chimeric antibody IDEC-C2B8 (rituximab). Arthritis Rheum. 2001, 44, 1717–1718. [Google Scholar] [CrossRef]
  39. Hellerstedt, B.; Ahmed, A. Delayed-type hypersensitivity reaction or serum sickness after rituximab treatment. Ann. Oncol. 2003, 14, 1792. [Google Scholar] [CrossRef]
  40. Finger, E.; Scheinberg, M. Development of serum sickness-like symptoms after rituximab infusion in two patients with severe hypergammaglobulinemia. J. Clin.Rheumatol. 2007, 13, 94–95. [Google Scholar] [CrossRef] [PubMed]
  41. Fong, L.; Small, E.J. Anti-cytotoxic T-lymphocyte antigen-4 antibody: The first in an emerging class of immunomodulatory antibodies for cancer treatment. J. Clin. Oncol. 2008, 26, 5275–5283. [Google Scholar] [CrossRef] [PubMed]
  42. Mir, T.; Al-Masalmeh, N.; Ambreen, S. Acute pneumonitis due to nivolumab and ipilimumab combination. Am. J. Ther. 2022, 29, e126–e128. [Google Scholar] [CrossRef]
  43. Zhu, S.; Fu, Y.; Zhu, B.; Zhang, B.; Wang, J. Pneumonitis induced by immune checkpoint inhibitors: From clinical data to translational investigation. Front. Oncol. 2020, 10, 1785. [Google Scholar] [CrossRef] [PubMed]
  44. Su, Q.; Zhu, E.C.; Wu, J.-B.; Li, T.; Hou, Y.-L.; Wang, D.-Y.; Gao, Z.-H. Risk of pneumonitis and pneumonia associated with immune checkpoint inhibitors for solid tumors: A systematic review and meta-analysis. Front. Immunol. 2019, 10, 108. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Winkler, U.; Jensen, M.; Manzke, O.; Schulz, H.; Diehl, V.; Engert, A. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 1999, 94, 2217–2224. [Google Scholar] [CrossRef]
  46. Nooka, A.K.; Gleason, C.; Ollivierre Sargeant, M.; Walker, M.; Watson, M.; Panjic, E.H.; Lonial, S. Managing infusion reactions to new monoclonal antibodies in multiple myeloma: Daratumumab and elotuzumab. J. Oncol. Pract. 2018, 14, 414–422. [Google Scholar] [CrossRef]
  47. Huang, A.; Xu, Y.; Zang, X.; Wu, C.; Gao, J.; Sun, X.; Xie, M.; Ma, X.; Deng, H.; Song, J.; et al. Beigelman-Aubry, C. Radiographic features and prognosis of early- and late-onset non-small cell lung cancer immune checkpoint inhibitor-related pneumonitis. BMC Cancer 2021, 21, 634. [Google Scholar] [CrossRef]
  48. Pozzessere, C.; Bouchaab, H.; Jumeau, R.; Letovanec, I.; Daccord, C.; Bourhis, J.; Prior, J.O.; Peters, S.; Lazor, R.; Beigelman-Aubry, C. Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: A retrospective study. ERJ Open Res. 2020, 6, 00165–02019. [Google Scholar] [CrossRef]
  49. Nishino, M.; Giobbie-Hurder, A.; Hatabu, H.; Ramaiya, N.H.; Hodi, F.S. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: A systematic review and meta-analysis. JAMA Oncol. 2016, 2, 1607–1616. [Google Scholar] [CrossRef] [Green Version]
  50. Lioté, H.; Lioté, F.; Séroussi, B.; Mayaud, C.; Cadranel, J. Rituximab-induced lung disease: A systematic literature review. Eur. Respir. J. 2010, 35, 681–687. [Google Scholar] [CrossRef] [Green Version]
  51. Han, S.; Rama, K.; Mallampalli, R.K. The acute respiratory distress syndrome: From mechanism to translation. J. Immunol. 2015, 194, 855–860. [Google Scholar] [CrossRef] [Green Version]
  52. Meduri, G.U.; Annane, D.; Chrousos, G.P.; Marik, P.E.; Sinclair, S.E. Activation and regulation of systemic inflammation in ARDS: Rationale for prolonged glucocorticoid therapy. Chest 2009, 136, 1631–1643. [Google Scholar] [CrossRef]
  53. Kounis, N.G.; Soufras, G.D.; Tsigkas, G.; Hahalis, G. Adverse cardiac events to monoclonal antibodies used for cancer therapy. Oncoimmunology 2014, 3, e27987. [Google Scholar] [CrossRef] [Green Version]
  54. Fabbrocini, G.; Cameli, N.; Romano, M.C.; Mariano, M.; Panariello, L.; Bianca, D.; Monfrecola, G. Chemotherapy and skin reactions. J. Exp. Clin. Cancer Res. 2012, 31, 50. [Google Scholar] [CrossRef] [Green Version]
  55. Maude, S.L.; Barrett, D.; Teachey, D.; Grupp, S.A. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014, 20, 119–122. [Google Scholar] [CrossRef]
  56. Daver, N.; McClain, K.; Allen, C.E.; Parikh, S.A.; Otrock, Z.; Rojas-Hernandez, C.; Blechacz, B.; Wang, S.; Minkov, M.; Jordan, M.B.; et al. A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults. Cancer 2017, 123, 3229–3240. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Thapa, S.; Shrestha, U. Immune Reconstitution Inflammatory Syndrome. Available online: https://www.ncbi.nlm.nih.gov/books/NBK567803/ (accessed on 14 December 2021).
  58. Malissen, N.; Lacotte, J.; Du-Thanh, A.; Gaudy-Marqueste, C.; Guillot, B.; Grob, J.-J. Macrophage activation syndrome: A new complication of checkpoint inhibitors. Eur. J. Cancer 2017, 77, 88–89. [Google Scholar] [CrossRef]
  59. Crayne, C.B.; Albeituni, S.; Nichols, K.E.; Cron, R.Q. The immunology of macrophage activation syndrome. Front. Immunol. 2019, 10, 119. [Google Scholar] [CrossRef] [Green Version]
  60. Cortese, I.; Reich, D.S.; Nath, A. Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease. Nat. Rev. Neurol. 2021, 17, 37–51. [Google Scholar] [CrossRef]
  61. Feske, S.K. Posterior reversible encephalopathy syndrome: A review. Semin. Neurol. 2011, 31, 202–215. [Google Scholar] [CrossRef] [PubMed]
  62. Druey, K.M.; Greipp, P.R. Narrative review: The systemic capillary leak syndrome. Annals Intern. Med. 2010, 153, 90–98. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Kaukonen, K.-M.; Bailey, M.; Pilcher, D.; Cooper, D.J.; Bellomo, R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N. Engl. J. Med. 2015, 372, 1629–1638. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Howard, S.C.; Jones, D.P.; Pui, C.-H. The tumor lysis syndrome. N. Engl. J. Med. 2002, 364, 1844–1854. [Google Scholar] [CrossRef]
  65. Kaplon, H.; Reichert, J.M. Antibodies to watch in 2021. MABS 2021, 13, e1860476. [Google Scholar] [CrossRef]
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Figure 1. Evolution of the development of therapeutic monoclonal antibodies from murine to fully human proteins to avoid unwanted immunogenicity. The iterative process proceeded stepwise through chimeric constructs incorporating mouse immunoglobulin variable regions into constant regions of human immunoglobulins and via humanized antibodies by substituting mouse complementarity determining regions (CDRs) in place of human sequences. Fully human antibodies have been developed with the application of phage display and transgenic mice technologies. Reproduced with permission from Baldo BA. Safety of biologics therapy. Monoclonal antibodies, cytokines, fusion proteins, hormones, enzymes, coagulation proteins, vaccines, botulinum toxins. Cham, Switzerland: Springer Nature; 2016 [3].
Figure 1. Evolution of the development of therapeutic monoclonal antibodies from murine to fully human proteins to avoid unwanted immunogenicity. The iterative process proceeded stepwise through chimeric constructs incorporating mouse immunoglobulin variable regions into constant regions of human immunoglobulins and via humanized antibodies by substituting mouse complementarity determining regions (CDRs) in place of human sequences. Fully human antibodies have been developed with the application of phage display and transgenic mice technologies. Reproduced with permission from Baldo BA. Safety of biologics therapy. Monoclonal antibodies, cytokines, fusion proteins, hormones, enzymes, coagulation proteins, vaccines, botulinum toxins. Cham, Switzerland: Springer Nature; 2016 [3].
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Figure 2. Cutaneous (hypersensitivity) vasculitis, also known as cutaneous small-vessel vasculitis and cutaneous leukocytoclastic vasculitis. Author James Heilman MD. CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons (accessed on 14 December 2021).
Figure 2. Cutaneous (hypersensitivity) vasculitis, also known as cutaneous small-vessel vasculitis and cutaneous leukocytoclastic vasculitis. Author James Heilman MD. CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons (accessed on 14 December 2021).
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Figure 3. Erythema multiforme with circumscribed bullous lesions. Image courtesy of Dr Adrian Mar.
Figure 3. Erythema multiforme with circumscribed bullous lesions. Image courtesy of Dr Adrian Mar.
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Figure 4. Papulopustular (acneiform) eruption on a patient during treatment with panitumumab, targeted to epidermal growth factor receptor (EGFR). From Fabbrocini, G.; Cameli, N.; Romano, M.C.; et al. Chemotherapy and skin reactions. J. Exp. Clin. Cancer Res. 2012, 31, 50. DOI: 10.1186/1756-9966-31-50 [54], an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0) (accessed on 14 December 2021).
Figure 4. Papulopustular (acneiform) eruption on a patient during treatment with panitumumab, targeted to epidermal growth factor receptor (EGFR). From Fabbrocini, G.; Cameli, N.; Romano, M.C.; et al. Chemotherapy and skin reactions. J. Exp. Clin. Cancer Res. 2012, 31, 50. DOI: 10.1186/1756-9966-31-50 [54], an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0) (accessed on 14 December 2021).
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Antibodies 11 00017 g005 550
Figure 5. Numbers of mAbs approved by the FDA and/or EMA during the 24 year period 1997–2020. Biosimilar and Fc fusion proteins are not included. Note that in 2021, 14 mAb products were approved. *: Data publicly available as of 25 November 2020. From Kaplon, H.; Reichert, J.M. Antibodies to watch in 2021. Mabs 2021, 13, e1860476, doi.org/10.1080/19420862.2020.1860476 [65], an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0) (accessed on 14 December 2021).
Figure 5. Numbers of mAbs approved by the FDA and/or EMA during the 24 year period 1997–2020. Biosimilar and Fc fusion proteins are not included. Note that in 2021, 14 mAb products were approved. *: Data publicly available as of 25 November 2020. From Kaplon, H.; Reichert, J.M. Antibodies to watch in 2021. Mabs 2021, 13, e1860476, doi.org/10.1080/19420862.2020.1860476 [65], an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0) (accessed on 14 December 2021).
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Table
Table 1. Therapeutic monoclonal antibodies for non-cancer therapy currently marketed with regulatory approval from the U.S. FDA or EMA or both (as at December 2021).
Table 1. Therapeutic monoclonal antibodies for non-cancer therapy currently marketed with regulatory approval from the U.S. FDA or EMA or both (as at December 2021).
Monoclonal Antibody INN and Trade NamesAntibody TypeTargetApproved Indications
Human–Mouse Chimeric
(-ximab)
Abciximab (ReoPro®)Chimeric IgG FabGlycoprotein IIb/IIIaAdjunct therapy for prevention of cardiac ischemic
complications
Basiliximab (Simulect®)Chimeric IgG1α-chain IL-2 receptor (CD25)Prevent organ transplant
rejection
Infliximab (Remicade®)Chimeric IgG1TNFCrohn’s disease; ulcerative
colitis; RA; ankylosing
spondylitis; psoriatic arthritis; plaque psoriasis
Obiltoxaximab (Anthim®)Chimeric IgG1Bacillus anthracis PAInhalational anthrax Bacillus
anthracis PA
Humanized (-zumab)
Alemtuzumab (Lemtrada®)Humanized IgG1CD52Lemtrada®: multiple sclerosis
Benralizumab (Fasenra®)Humanized IgG1
(afucosylated)		IL-5RαAsthma
Bimekizumab (Bimzelx®)Humanized IgG1IL-17A, IL-17F, IL-17AFPlaque psoriasis
Brolucizumab (Beovu®)Humanized single-chain
(scFv) fragment		VEGF-ANeovascular (wet) age-related macular degeneration
Caplacizumab-yhdp (Caplivi®)Humanized bivalent single-domain nanobodyvon Willebrand factor (vWF)Acquired thrombotic thrombocytopenic purpura
Certolizumab pegol (Cimzia®)Humanized IgG1 Fab,
pegylated		TNFCrohn’s disease; RA
Crizanlizumab-tmca
(Adakveo®)		Humanized IgG2P-selectinSickle cell disease
Daclizumab (Zinbryta®)Humanized IgG2α-chain IL-2 receptor (CD25)Multiple sclerosis
Eculizumab (Soliris®)Humanized IgG2/4Complement C5Paroxysmal nocturnal hemoglobinuria; atypical hemolytic uremic syndrome; neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4)
antibody-positive
Emicizumab-kxwh (Hemlibra®)Humanized IgG4 bispecificFactors IXa and XHemophilia A
Eptinezumab-jjmr (Vyepti®)Humanized IgG1CGRPMigraine
Fremanezumab-vfrm (Ajovy®)Humanized IgG4CGRPMigraine
Galcanezumab-gnlm
(Emgality®)		Humanized IgG4CGRPMigraine
Ibalizumab-uiyk (Trogarzo®)Humanized IgG4CD4HIV-1 infection
Idarucizumab (Praxbind®)Humanized IgG1
antibody fragment Fab		DabigatranReversal of anticoagulant
effects of dabigatran; life-threatening or uncontrolled bleeding
Inebilizumab-cdon (Uplizna®)Humanized afucosylated
IgG1		CD19Neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive
Ixekizumab (Taltz®)Humanized IgG4IL-17APlaque psoriasis; psoriatic
arthritis
Mepolizumab (Nucala®)Humanized IgG1IL-5Asthma; eosinophilic granulomatosis with polyangiitis
Natalizumab (Tysabri®)Humanized IgG4α4 integrin (binds to α4β1 and α4β7 integrins)Multiple sclerosis; Crohn’s
disease
Ocrelizumab (Ocrevus®)Humanized IgG1CD20Multiple sclerosis
Omalizumab (Xolair®)Humanized IgG1IgEPersistent asthma; chronic
idiopathic urticaria
Palivizumab (Synagis®)Humanized IgG1RSVFPrevention of lower respiratory tract disease RSV in children
Ranibizumab (Lucentis®)Humanized IgG1 FabVEGF-ANeovascular (wet) age-related macular degeneration; macular edema following retinal vein
occlusion; diabetic macular edema
Ravulizumab-cwvz (Ultomiris®)Humanized IgG2/4Complement C5Paroxysmal nocturnal hemoglobinuria
Reslizumab (Cinqair®)Humanized IgG4IL-5Asthma
Risankizumab-rzaa (Skyrizi®)Humanized IgG1IL-23 p19Plaque psoriasis
Romosozumab-aqqg (Evenity®)Humanized IgG2SclerostinOsteoporosis
Satralizumab-mwge
(Enspryng®)		Humanized IgG2IL-6RNeuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody-positive
Tildrakizumab-asmn
(Ilumetri®; Ilumya®)		Humanized IgG1IL-23 p19Plaque psoriasis
Tocilizumab (Actemra®;
RoActemra®)		Humanized IgG1IL-6RRA; polyarticular juvenile
idiopathic arthritis; systemic
juvenile idiopathic arthritis
Vedolizumab (Entyvio®)Humanized IgG1α4β7 integrinAdult ulcerative colitis; adult Crohn’s disease
Fully human (-umab)
Adalimumab (Humira®)Human IgG1TNFRA; psoriatic arthritis;
ankylosing spondylitis; plaque psoriasis; Crohn’s disease
Aducanumab-avwa
(Aduhelm®)		Human IgG1Amyloid betaAlzheimer’s disease
Alirocumab (Praluent®)Human IgG1PCSK9Heterozygous FH; atherosclerotic CV disease requiring additional ↓ of LDL-C
Anifrolumab-fnia (Saphnelo®)Human IgG1Subunit I type I interferon
receptor (IFNAR)		Systemic lupus erythematosis
Ansuvimab-zykl (Ebanga®)Human IgG1Zaire ebolavirus (EBOV)
glycoprotein 1 (GP1)		Zaire ebolavirus infection
Atoltivimab, Maftivimab
and Odesivimab-ebgn
(Inmazeb®)		Human IgG1Zaire ebolavirus (EBOV)
glycoprotein 1 (GP1)		Zaire ebolavirus infection
Belimumab (Benlysta®)Human IgG1BlySSystemic lupus erythematosus
Bezlotoxumab (Zinplava®)Human IgG1Clostridium difficile toxin BRecurrence of Clostridium difficile toxin B infection
Brodalumab (Siliq®;
Kyntheum®; Lumicef®)		Human IgG2IL-17RAPlaque psoriasis
Burosumab-twza (Crysvita®)Human IgG1FGF23X-linked hypophosphatemia
Canakinumab (Ilaris®)Human IgG1IL-1βCryopyrin-associated periodic syndromes (CAPS) including familial cold autoinflammatory and Muckle–Wells syndromes; SJIA with body weight ≥7.5 kg; NOMID/CINCA; FCAS/FCU; gouty arthritis
Casirivimab + Imdevimab
(REGEN-COV®; Ronapreve®)		Human IgG1The 2 mAbs bind to separate epitopes of the spike protein RBD of SARS-CoV-2, thus
preventing its binding to the
human ACE2 receptor and
subsequent cell entry		COVID-19 disease
Denosumab (Prolia®)Human IgG2RANKLBone loss—for osteoporosis and to increase bone mass in menopausal women at high risk of fracture
Dupilumab (Dupixent®)Human IgG4IL-4Rα subunitAtopic dermatitis
Efgartigimod-alfa-fcab
(Vyvgart®)		Human IgG1 Fc fragmentNeonatal Fc receptor FcRnGeneralized myasthenia gravis
Emapalumab-lzsg (Gamifant®)Human IgG1IFNγHLH
Erenumab-zooe (Aimovig®)Human IgG2CGRP receptorMigraine
Evinacumab-dgnb (Evkeeza®)Human IgG4ANGPTL3 (angiopoietin-like 3)Homozygous familial
hypercholesterolemia (HoFH)
Evolocumab (Repatha®)Human IgG2PCSK9Primary hyperlipidemia and mixed dyslipidemia;
homozygous FH to reduce
LDL-C and other lipids
Golimumab (Simponi®)Human IgG1TNFRA; psoriatic arthritis (both in combination with methotrexate); ankylosing spondylitis
Guselkumab (Tremfya®)Human IgG1IL-23Plaque psoriasis
Lanadelumab-flyo (Takhzyro®)Human IgG1Plasma kallikreinHAE prevention
Raxibacumab (ABthrax®)Human IgG1 Bacillus anthracis PAInhalational anthrax to Bacillus anthracis and prophylaxis in
absence of alternative
therapies
Regdanvirimab (Regkirona®)Human IgG1mAb binds to the spike protein RBD of SARS-CoV-2 preventing its binding to the human ACE2 receptor and subsequent cell
entry		COVID-19 disease
Sarilumab (Kevzara®)Human IgG1IL-6RRA
Secukinumab (Cosentyx®)Human IgG1IL-17AModerate to severe plaque
psoriasis
Sotrovimab
(Xevudy®) 1		Human IgG1Spike protein RBD of SARS-CoV-2COVID-19 disease
Teprotumumab-trbw
(Tepezza®)		Human IgG1IGF-1RThyroid eye disease
Tezepelumab-ekko (Tezspire®)Human IgG2Thymic stromal lymphopoietinSevere asthma
Tralokinumab (Adtralza®)Human IgG4IL-13Atopic dermatitis
Ustekinumab (Stelara®)Human IgG1IL-12, IL-23Plaque psoriasis
ACE2—angiotensin-converting enzyme 2; ADCC—antibody-dependent cell-mediated cytotoxicity; BlyS—B lymphocyte stimulator, also known as B cell-activating factor, BAFF; C5—complement component 5; CDC—complement-dependent cytotoxicity; CGRP—calcitonin gene-related peptide; CHO—Chinese hamster ovary cells; CINCA—chronic infantile neurological, cutaneous, articular syndrome; COVID—coronavirus disease; CV—cardiovascular; EMA—European Medicines Agency; FCAS—familial cold autoinflammatory syndrome; FCU—familial cold urticaria; FDA—U.S. Food and Drug Administration; FH—familial hypercholesterolemia; FGF23—fibroblast growth factor 23; GI—gastrointestinal; HAE—hereditary angioedema; HIV—human immunodeficiency virus; HLH—primary hemophagocytic lymphohistiocytosis; IGF-1R—insulin-like growth factor-1 receptor; IPP—International Nonproprietary Name; LDL—low-density lipoprotein; LDL-C—LDL-cholesterol; LDLR—LDL receptor; NLRP-3—gene cryopyrin or nucleotide-binding domain, leucine rich family, pyrin domain-containing 3 gene; NOMID—neonatal-onset multisystem inflammatory disease; NSCLC—non-small cell lung cancer; NSO—non-Ig-secreting, non-L chain-synthesizing, 8-azaguanine-resistant and HAT-sensitive mouse myeloma cell line; PA—protective antigen of B. anthracis toxin; PCSK9—proprotein convertase subtilisin/kexin type 9; RA—rheumatoid arthritis; RANKL—receptor activator of nuclear factor kappa-B ligand (CD254), a member of the TNF cytokine family; RBD—receptor-binding domain; RSV—human respiratory syncytial virus (F viral protein coat antigen); SARS-CoV-2—severe acute respiratory syndrome coronavirus 2; SJIA—active systemic juvenile idiopathic arthritis; Sp2/0—BALB/c mouse spleen cells fused with P3 myeloma. Cells do not secrete Ig, are resistant to 8-azaguanine, and are HAT-sensitive; TNF— tumor necrosis factor; VEGF—vascular endothelial growth factor (a subfamily of growth factors; includes VEGF-A); VEGFR2—vascular endothelial growth factor receptor 2, also known as KDR (kinase insert domain-containing receptor), FLK1 (fetal liver kinase 1), or CD309. 1 Note added in press: Approved by the FDA 17 December 2021. ↓ decrease.
Table
Table 2. Therapeutic monoclonal antibodies for cancer therapy currently marketed with regulatory approval from the U.S. FDA or EMA or both (as at December 2021).
Table 2. Therapeutic monoclonal antibodies for cancer therapy currently marketed with regulatory approval from the U.S. FDA or EMA or both (as at December 2021).
Monoclonal Antibody INN and Trade NameType of mAbTargetApproved Indications
Rat-mouse chimera (-axomab)
Catumaxomab (Removab®)Rat IgG2b/Mouse IgG2a
bispecfic		EpCAM/CD3Malignant ascites
Mouse (-omab)
Blinatumomab (Blincyto®)Mouse scFvκ-H bispecificCD19/CD3 epsilonPhiladelphia chromosome-negative relapsed or refractory B cell precursor acute lymphoblastic leukemia
Ibritumomab tiuxetan
(Zevalin®)		Mouse IgG1CD20Non-HL
Moxetumomab pasudox–
tdfk (Lumoxiti®)		ADC immunotoxin. Mouse
single chain variable domain
(scFv)		CD22HCL
Human-mouse chimeric
(-ximab)
Brentuximab vedotin
(Adcetris®)		Chimeric IgG1CD30HL after failure of stem cell transplant or chemotherapy; sALCL after failure of chemotherapy; post auto-HSCT consolidation treatment for HL
Cetuximab (Erbitux®)Chimeric IgG1EFGRColorectal and head and neck
cancers
Dinutuximab (Unituxin®)Chimeric IgG1GD2Pediatric patients with high-risk neuroblastoma
Isatuximab-irfc (Sarclisa®)Chimeric IgG1
with 2 identical H
and κ L chains		CD38MM
Margetuximab-cmkb
(Margenza®)		Chimeric IgG1HER2HER2-positive breast cancer
Rituximab
(Rituxan®; MabThera®)		Chimeric IgG1CD20Non-HL; CLL; rheumatoid
arthritis; Wegener’s
granulomatosis; microscopic
polyangiitis
Siltuximab (Sylvant®)Chimeric IgG1IL-6Multicentric Castelman’s disease in patients negative for HIV and HHV-8
Humanized (-zumab)
Ado-trastuzumab emtansine (Kadcyla®)ADC. Humanized IgG1HER2HER2-positive breast cancer in
patients who previously received trastuzumab or a taxane
Alemtuzumab (Campath®;
MabCampath®) 		Humanized IgG1CD52Campath, MabCampath: B cell CLL
Atezolizumab (Tecentriq®)Humanised IgG1PD-L1MUC; NSCLC
Bevacizumab (Avastin®)Humanized IgG1VEGF-AMetastatic colorectal cancer; non-squamous NSCLC; metastatic breast cancer; ovarian cancer;
glioblastoma
Dostarlimab-gxly (Jemperli®)Humanized IgG4PD-1Endometrial cancer
Elotuzumab (Empliciti®)Humanised IgG1SLAMF7MM
Fam-trastuzumab
deruxtecan-nxki (Enhertu®)		ADC. Humanised IgG1HER2HER2-positive breast, gastric, and GE adenocarcinomas
Gemtuzumab ozogamicin
(Mylotarg®)		ADC. Humanized IgG4CD33AML
Inotuzumab ozogamicin
(Besponsa®)		ADC. Humanized IgG4CD22ALL
Loncastumab tesirine-lpyl
(Zynlonta®)		ADC. Humanized IgG1CD19 with teserine cytotoxic
agent		LBCL including DLBCL
Mogamulizumab-kpkc
(Poteligeo®)		Humanized IgG1CCR4Mycosis fungoides; Sézary
syndrome
Naxitamab-gqgk
(Danyelza®)		Humanized IgG1GD2Neuroblastoma—antibody given in combination with GM-CSF
Obinutuzumab
(Gazyva®; Gazyvaro®)		Humanized IgG1CD20In combination with chlorambucil for previously untreated CLL
Pembrolizumab (Keytruda®)Humanized IgG4PD-1Unresectable or metastatic
melanoma; refractory metastatic NSCLC tumors that express PD-L1
Pertuzumab (Perjeta®)Humanized IgG1HER2Combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer
Polatuzumab
vedotin-piiq (Polivy®)		ADC. Humanized IgG1CD79bDiffuse large B cell lymphoma
Sacituzumab govitecan-hziy
(Trodelvy®)		ADC. Humanized IgG1Trop-2 with topoisomerase inhibitormTNBC
Tafasitamab-cxix (Monjuvi®)Humanized IgG1/2 with hybrid Fc-modified domainCD19DLBCL
Trastuzumab (Herceptin®)Humanized IgG1HER2Breast cancer overexpressing HER2, metastatic gastric or GE junction adenocarcinoma
overexpressing HER2
Fully human (-umab)
Amivantamab-vmjw
(Rybrevant®)		Bi-specific low fucose human
IgG1-based antibody		EGFR and c-MET receptorsNSCLC
Avelumab (Bavencio®)Human IgG1PD-L1MCC; UC; RCC
Belantamab mafodoton-blmf
(Blenrep®)		ADC afucosylated
IgG1		BCMA with MMAF
microtubule inhibitor		MM
Cemiplimab-rwlc (Libtayo®)Human IgG4PD-1CSCC
Daratumumab (Darzalex®)Human IgG1CD38MM
Denosumab
(Prolia®; Xgeva®)		Human IgG2RANKLBone loss. Prolia: for osteoporosis and to increase bone mass; Xgeva: for bone metastases from solid
tumors and giant cell tumor of bone
Durvalumab (Imfinzi®)Human IgG1PD-L1UC
Enfortumab-vedotin-ejfv
(Padcev®)		ADC human IgG1Nectin-4 with MMAE
microtubule inhibitor		UC
Ipilimumab (Yervoy®)Human IgG1CTLA-4Metastatic melanoma
Necitumumab (Portrazza®)Human IgG1EGFRSquamous NSCLC
Nivolumab (OPDIVO®)Human IgG4PD-1Unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600-positive, a BRAF
inhibitor; NSCLC
Ofatumumab (Arzerra®)Human IgG1CD20CLL refractory to fludarabine and alemtuzumab
Olaratumab (Lartruvo®)Human IgG1PDGFR-αSoft tissue sarcoma
Panitumumab (Vectibix®)Human IgG2EGFRMetastatic colorectal cancer
Ramucirumab (Cyramza®)Human IgG1VEGFR2Gastric or GE junction adeno-
carcinoma; metastatic NSCLC with docetaxel after platinum therapy; HCC; with FOLFIRI for metastatic colorectal cancer
Tisotumab vedotin-tftv
(Tivdak®)		ADC human IgG1TF with MMAE microtubule
inhibitor		Cervical cancer
ADC—antibody drug conjugate; ALL—acute lymphoblastic leukemia; auto-HSCT—autologous hematopoietic stem cell transplantation; BRAF—proto-oncogene B-Raf; C5—complement component 5; CLL—chronic lymphocytic leukemia; CTLA-4—cytotoxic T lymphocyte-associated antigen 4 or CD152; CSCC—cutaneous squamous cell carcinoma; DLBCL—diffuse large B cell lymphoma; EGFR—epidermal growth factor receptor; EMA—European Medicines Agency; EpCAM—epithelial cell adhesion molecule; FDA—U.S. Food and Drug Administration; FOLFIRI—combination of folinic acid (leucovorin), fluorouracil, and irinotecan; GD2—glycolipid disialoganglioside on neuroblastoma, central nervous system, and peripheral nerve cells; GE—gastroesophageal; HCC—hepatocellular carcinoma; HCL—hairy cell leukemia; HER2—human epidermal growth factor receptor 2, also known as HER2/neu, ErbB2, CD340, p185, or EGFR2; HL—Hodgkin lymphoma; IPP—International Nonproprietary Name; LBCL—large B cell lymphoma; MCC—Merkel cell carcinoma; MM—multiple myeloma; MMAE—cytotoxic agent monomethyl auristatin E; MMAF—cytotoxic agent monomethyl auristatin F; mTNBC—metastatic triple-negative breast cancer; MUC—metastatic urothelial carcinoma; NSCLC—non-small cell lung cancer; PD-1—programmed cell death protein 1 or CD279; PD-L1—programmed cell death protein ligand 1; RANKL—receptor activator of nuclear factor kappa-B ligand (CD254), a member of the TNF cytokine family; RCC—renal cell carcinoma; sALCL—systemic anaplastic large cell lymphoma; teserine—also known as SG3249, a pyrrolobenzodiazepine dimer; TF—tissue factor, platelet tissue factor, factor III, CD142; Trop-2—trophoblast cell surface antigen-2; UC—urothelial carcinoma; VEGF—vascular endothelial growth factor (a subfamily of growth factors; includes VEGF-A); VEGFR2—vascular endothelial growth factor receptor 2, also known as KDR (kinase insert domain-containing receptor), FLK1 (fetal liver kinase 1), or CD309.
Table
Table 3. Targets with more than one complementary approved therapeutic monoclonal antibody.
Table 3. Targets with more than one complementary approved therapeutic monoclonal antibody.
TargetMonoclonal Antibodies
Monoclonal antibodies for non-cancer therapy
TNFAdalimumab; certolizumab pegol; golimumab; infliximab
PCSK9Alirocumab; evolocumab
EBOV GP1Ansuvimab-zykl; atoltivimab; maftivimab; odesivimab-ebgn
IL-2 receptor α chain (CD25)Basiliximab; daclizumab
VEGF-ABrolocizumab-dbll; ranibizumab
ACE2 RBD of SARS-CoV-2Casirivimab + imdevimab; regdanvirimab;
Sotrovimab
Complement C5Eculizumab; ravulizumab-cwvz
CGRPEptinezumab-jjmr; fremanezumab-vfrm; galcanezumab-gnlm
IL-17AIxekizumab; secukinumab
IL-5Mepolizumab; reslizumab
α4 integrinNatalizumab; vedolizumab
Bacillus anthracisObiltoxaximab; raxibacumab
IL-23 p19Risankizumab-rzaa; tildrakizumab-asmn
IL-6RSarilumab; satralizumab-mwge; tocilizumab
Monoclonal antibodies for cancer therapy
HER2Ado-trastuzumab; fam-trastuzumab; margetuximab-cmkb; pertuzumab; trastuzumab
PD-L1Atezolizumab; avelumab; durvalumab
PD-1Cemiplimab-rwlc; dostarlimab-gxly; nivolumab; pembrolizumab
EGFRAmivantamab; Cetuximab; necitumumab; panitumumab
CD38Daratumumab; isatuximab-irfc
GD2Dinutuximab; naxitamab-gqgk
CD20Ibritumomab; obinutuzumab; ofatumumab; rituximab
CD22Inotuzumab ozogamicin; moxetumomab pasudox-tdfk
For expansion of target abbreviations, see Table 1 and Table 2.
Table
Table 4. Adverse events associated with approved 1 monoclonal antibodies used for non-cancer therapies (as at December 2021).
Table 4. Adverse events associated with approved 1 monoclonal antibodies used for non-cancer therapies (as at December 2021).
Monoclonal Antibody 2 INN and Trade NamesTarget 3Warnings, Precautions, Risks and Safety ConcernsOther Adverse Events 4, Serious and Common
Abciximab (ReoPro®)Glycoprotein IIb/IIIaIncreased risk of bleeding; thrombocytopeniaSystemic: Bleeding; intracranial hemorrhage or stroke; GI; CV; anemia; NS; respiratory; urinary disorders
Cutaneous: Pruritus; generalized exanthema
Adalimumab (Humira®)TNFBoxed warning: Serious
infections; malignancy
Other: Anaphylaxis, serious allergic reactions; hepatitis B reactivation; demyelinating disease; cytopenias; heart
failure; lupus-like syndrome		Systemic: Infections; isr; ILD; sarcoidosis; liver failure
Cutaneous: SJS; EM; psoriasis; cutaneous vasculitis; alopecia
Aducanumab-avwa (Aduhelm®)Amyloid betaAmyloid-related imaging
abnormalities (ARIA);
hypersensitivity		Systemic: Headache; ARIA-oedema, -headache, -H microhemorrhage, -H superficial siderosis, fall
Alemtuzumab (Lemtrada®)CD52Boxed warning: Autoimmunity; IRs; malignancies
Other: Other immune
cytopenias; glomerular nephropathies; thyroid disorders; delay therapy in cases of infections; pneumonitis		Systemic: Headache; pyrexia; nausea; UTI; herpes virus
infection; extremity and back pain; dizziness; flushing; cough; chills; vomiting;
dyspnea
Cutaneous: Rash; urticaria;
pruritus; dermatitis
Alirocumab (Praluent®)PCSK9Allergic reactions (pruritus, urticaria, rash) including some serious (including
hypersensitivity vasculitis)		Systemic: Nasopharyngitis; isr; influenza; URTI; cough; sinusitis; bronchitis; diarrhea; myalgia; muscle spasms; musculoskeletal pain; liver enzyme abnormalities
Anifrolumab-fnia (Saphnelo®)IFNARSerious infections; hypersensitivity; malignancy; avoid live attenuated vaccines and other biological therapies Systemic: Nasopharyngitis; URTI; IR; bronchitis; herpes zoster; cough
Ansuvimab-zykl (Ebanga®)EBOV GP1Hypersensitivity; IRSystemic: Pyrexia; tachycardia; diarrhea; vomiting; hypotension; tachypnoea; chills
Atoltivimab, Maftivimab, and Odesivimab-ebgn
(Inmazeb®)		EBOV GP1Hypersensitivity; IRSystemic: Pyrexia; chills;
tachycardia; tachypnoea;
vomiting
Basiliximab (Simulect®)IL-2 receptor α-chain (CD25)Boxed warning: General risk of immunosuppressive therapy
Other: Immunogenicity;
hypersensitivity		Systemic: GI; viral infection; peripheral oedema; UTI; URTI; dyspnea; wound
complications; hypertension; anemia; hypo- and hyperkalemia and hyperuricemia; headache; tremor
Cutaneous: Rash; pruritus;
hypertrichosis
Belimumab (Benlysta®)BLySMortality; serious infection; malignancy; hypersensitivity including anaphylaxis; IR;
depression; immunization		Systemic: Nausea; diarrhea; pyrexia; pain in extremity;
bronchitis; depression;
migraine
Cutaneous: Rash; pruritus
Benralizumab (Frasenra®)IL-5RαHypersensitivity; helminth infections—treat prior;
decrease steroids gradually		Systemic: Headache;
pharyngitis
Bezlotoxumab (Zinplava®)Clostridium difficile toxin BHeart failureSystemic: Nausea; pyrexia; headache
Bimekizumab (Bimzelx®)IL-17A, IL-17F, IL-17AFInfections; pre-evaluation for tuberculosis; IBD; avoid live vaccines; hypersensitivitySystemic: Infections and
infestations, nervous system disorders; isr
Cutaneous: Dermatitis; acne; eczema
Brodalumab (Siliq®; Kyntheum®; Lumicef®)IL-17RABoxed warning: Suicidal
ideation and behavior.
Other: TB; infections; Crohn’s disease; avoid live vaccines		Systemic: Arthralgia; headache; fatigue; diarrhea; oropharyngeal pain; nausea;
myalgia; isr, influenza;
neutropenia; tinea infections
Brolucizumab-dbll (Beovu®)VEGF-AEndophthalmitis and retinal detachment; risk of arterial thromboembolic events; increase in intraocular pressureSystemic: Conjunctival
hemorrhage; eye pain;
vitreous floaters; cataracts; blurred vision
Burosumab-twza (Crysvita®)FGF23Hypersensitivity; isr; hyperphosphatemia and risk of nephrocalcinosisSystemic: Headache; isr;
vomiting; pyrexia; pain in
extremity; decreased vitamin D
Canakinumab
(Ilaris®)		IL-1βIncreased risk of serious
infections; immunization; MAS; hypersensitivity;
immunosuppression		Systemic: CAPS—Nasopharyngitis; diarrhea;
influenza; headache; nausea; dizziness/vertigo; SJIA, URTI, isr, abdominal pain
Caplacizumab-yhdp (Cablivi®)von Willibrand factorBleedingSystemic: Epistaxis; gingival bleeding; headache; isr
Casirivimab + Imdevimab
(REGEN-COV®; Ronapreve®)		mAbs bind to SARS-CoV-2 spike protein RBD preventing binding to the ACE2 receptor Hypersensitivity including anaphylaxis; IR-
Certolizumab pegol
(Cimzia®)		TNFBoxed warning: Serious
infections; lymphoma and other malignancies
Other: Heart failure; serious allergic reactions; hepatitis B reactivation; demyelinating disease; cytopenias; lupus-like syndrome		Systemic: URTI; cardiac
disorders; eye disorders; isr; hepatitis and ↑ liver
enzymes; nephrotic
syndrome; renal failure; thrombophlebitis; vasculitis
Cutaneous: Dermatitis;
erythema nodosum; urticaria
Crizanlizumab-tmca (Adakveo®)P-selectinIRSystemic: Nausea; arthralgia; back pain; pyrexia
Daclizumab (Zinbryta®)IL-2 receptor α-chain (CD25)Boxed warning: Hepatic injury including autoimmune
hepatitis and other immune-mediated disorders
Other: Hypersensitivity; infections; depression and suicide		Systemic: Nasopharyngitis; URTI; oropharyngeal pain; bronchitis; eczema;
depression; influenza.
Cutaneous: Dermatitis, rash
Denosumab (Prolia®)RANKLHypersensitivity; hypocalcemia; serious infections;
osteonecrosis of jaw; atypical femoral fractures; severe bone, joint, muscle pain;
suppression of bone turnover;
dermatologic reactions		Systemic: Post-menopausal
osteoporosis—back, extremity and musculoskeletal pain;
hypercholesterolemia;
cystitis; male osteoporosis—back pain; arthralgia;
nasopharyngitis
Cutaneous: Rash; pruritus;
dermatitis; eczema
Dupilumab (Dupixent®)IL-4RαHypersensitivity; conjunctivitis and keratitis; eosinophilic conditions; helminth
infections—treat prior;
decrease steroids gradually		Systemic: Conjunctivitis;
blepharitis; eye pruritus;
herpes infections; keratitis; dry eye; oropharyngeal pain; isr; eosinophilia
Eculizumab (Soliris®)Complement C5Boxed warning: Serious meningococcal infectionSystemic: PNH—headache; nasopharyngitis; back pain; nausea; AHUS—hypertension; URTI; GI; abdominal pain; anemia; cough; pyrexia; peripheral edema
Cutaneous: Rash; pruritus
Efgartigimod-alfa-fcab
(Vyvgart®) 5		Neonatal Fc receptor FcRnSee reference below 5See reference below 5
Emapalumab-lzsg (Gamifant®)IFNγInfections; IR; avoid live vaccinesSystemic: Infections; pyrexia;
hypertension; IR
Emicizumab-kxwh (Hemlibra®)Factors IXa & XBoxed warning: Thrombotic microangiopathy and thromboembolism. Other: mAb
interference with coagulation tests		Systemic: Arthralgia; isr;
headache
Eptinezumab-jjmr (Vyepti®)CGRPHypersensitivitySystemic: Nasopharyngitis; hypersensitivity
Erenumab-zooe (Aimoig®)CGRP Receptor-Systemic: Constipation; isr
Evinacumab-dgnb (Evkeeza®)ANGPTL3Serious hypersensitivity;
embryo-fetal toxicity		Systemic: Nasopharyngitis;
influenza-like illness;
dizziness; rhinorrhea; nausea
Evolocumab (Repatha®)PCSK9Patients with renal and
hepatic impairments have not yet been adequately studied; cover of prefilled syringe and pen contain latex which may cause allergic reactions		Systemic: Nasopharyngitis; isr; influenza; URTI; back pain; arthralgia;
hypertension; nausea
Cutaneous: Rash; hives
Fremanezumab-vfrm (Ajovy®)CGRPHypersensitivitySystemic: isr
Galcanezumab-gnlm (Emgality®)CGRPHypersensitivitySystemic: isr
Golimumab (Simponi®)TNFBoxed warning: Serious
infections; lymphoma, and other malignancies
Other: Invasive fungal
infections; heart failure;
hepatitis B reactivation;
demyelinating disease;
hypersensitivity		Systemic: URTI; viral
infections; bronchitis; ↑ liver
enzymes; sarcoidosis; ILD; paresthesia
Cutaneous: Skin exfoliation; rash
Guselkumab (Tremfya®)IL-23Infections; prior evaluation for TBSystemic: URTI; isr;
arthralgia; headache;
diarrhea; tinea; gastroenteritis; herpes simplex infections
Ibalizumab-uiyk (Trogarzo®)CD4IRISSystemic: Diarrhea, nausea; dizziness.
Cutaneous: Rash
Idarucizumab (Praxbind®)DabigatranThromboembolic risk; hypersensitivity; risk of adverse
reaction in patients with hereditary fructose intolerance; reappearance of bleeding		Systemic: Headache;
hypokalemia; delirium; pneumonia; constipation;
pyrexia
Inebilizumab-cdon (Uplizna®)CD19IR; infections; monitor
immunoglobulin levels; fetal risk		Systemic: Urinary tract
infection; arthralgia
Infliximab (Remicade®)TNFBoxed warning: Serious
infections; malignancy
Other: Hepatitis B
reactivation; hepatotoxicity;
cytopenias; demyelinating disease; lupus-like syndrome		Systemic: Infections;
pancytopenia; anemia;
cellulitis; serum sickness; thrombophlebitis; intestinal obstruction; ILD; anaphylaxis; IRs
Cutaneous: Cutaneous
vasculitis; SJS; EM; psoriasis;
Ixekizumab (Taltz®)IL-17AInfections: TB—evaluate prior; hypersensitivity; inflammatory bowel diseaseSystemic: URTI; isr; nausea; tinea infections
Lanadelumab-flyo (Takhzyro®)Plasma kallikreinHypersensitivitySystemic: URTI; isr; headache;
diarrhea; dizziness; myalgia
Cutaneous: Rash
Mepolizumab (Nucala®)IL-5Hypersensitivity; helminth
infections—treat prior; herpes zoster infections—consider prior vaccination; decrease steroids gradually; not to be used for bronchospasm or status
asthmaticus		Systemic: Headache; isr; back pain; fatigue
Natalizumab (Tysabri®)α4 integrin (binds to α4β1 and α4β7 integrins)Boxed warning: PML
Other: Hypersensitivity;
hepatotoxicity; immunosuppression/infections; IRIS		Systemic: MS—headache;
fatigue; arthralgia; urinary tract infection; URTI;
gastroenteritis; vaginitis;
diarrhea. CD—headache; URTI; nausea
Cutaneous: Rash; urticaria
Obiltoxaximab (Anthim®)Bacillus anthracis PABoxed warning: Hypersensitivity and anaphylaxisSystemic: URTI; headache;
pruritus; IR pain, swelling, bruise
Cutaneous: Urticaria
Ocrelizumab (Ocrevus®)CD20Infections; IR; increased risk of malignancySystemic: Respiratory tract
infections; IR; PML
Cutaneous: Skin infections
Omalizumab (Xolair®)IgEAnaphylaxis; malignancy; acute asthma; decrease CSs gradually; eosinophilia; serum sickness-like
reaction; parasitic infection		Systemic: Allergic asthma—
arthralgia; pain; dizziness;
fracture; earache. CIU—nausea; pharyngitis; URTI; sinusitis; arthralgia; headache; cough; virus infections
Cutaneous: Pruritus; dermatitis.
Palivisumab (Synagis®)RSVFAnaphylaxis; delay administration during moderate–severe
infections; give with caution in cases of thrombocytopenia or coagulation disorders		Systemic: isr; pyrexia; apnea; cough; dizziness thrombocytopenia
Cutaneous: Rash; itching;
erythema
Ranibizumab (Lucentis®)VEGF-AEndophthalmitis and retinal
detachment, increase in intraocular pressure and risk of arterial thromboembolic events after
intravitreal injection		Systemic: Conjunctival
hemorrhage; eye pain; vitreous floaters; cataracts
Ravulizumab-cwvz
(Ultomiris®)		Complement C5Boxed warning: Serious
meningococcal infections		Systemic: URTI; headache;
diarrhea; nausea
Raxibacumab (ABthrax®)Bacillus anthracis PAIRSystemic: Pain in extremity;
somnolence; headache; URTI; nausea; cough; arthralgias.
Cutaneous: Rash; pruritus;
urticaria
Regdanvirimab (Regkirona®)Binds to SARS-CoV-2 spike
protein RBD preventing
binding to ACE2 receptor		Hypersensitivity including
anaphylaxis; IR		--
Reslizumab (Cinqair®)IL-5Boxed warning: Anaphylaxis
Other: Helminth infections—treat prior; decrease steroids gradually; malignancy		Systemic: Oropharyngeal pain
Risankizumab-rzaa (Skyrizi®)IL-23 p19Infections; prior evaluation for TB; hypersensensitivitySystemic: URTI; isr; diarrhea
Romosozumab-aqqg (Evenity®)SclerostinBoxed warning: Potential risk of myocardial infarction, stroke, and cardiovascular death
Other: Cardiac events; hypersensitivity; hypocalemia; atypical femoral fracture		Systemic: Arthralgia; headache
Satralizumab-mwge (Enspryng®)IL-6RInfections; elevated liver
enzymes (ALT, AST); decreased neutrophils		Systemic: Nasopharyngitis; headache; URTI; gastritis;
arthralgia; extremity pain;
fatigue; nausea
Cutaneous: Rash
Sarilumab (Kevzara®)IL-6RBoxed warning: Risk of serious infection
Other: GI perforation; avoid live vaccines; hypersensitivity; neutropenia; thrombocytopenia		Systemic: increased ALT; isr; URTI; urinary tract infections
Secukinumab (Cosentyx®)IL-17AInfections; tuberculosis
activation; exacerbation of Crohn’s disease; hypersensitivity; avoid live vaccines		Systemic: Nasopharyngitis;
diarrhea; URTI; rhinitis
Cutaneous: Urticaria
Sotrovimab (Xevudy®) 6Spike protein RBD of SARS-CoV-2Hypersensitivity reactions
including anaphylaxis		--
Teprotumumab-trbw
(Tepezza®)		IGF-1RIR; exacerbation of pre-existing inflammatory bowel disease;
hyperglycemia		Systemic: Muscle spasm; nausea; alopecia; diarrhea; fatigue;
hyperglycemia; hearing impairment; dry skin; dysgeusia;
headache
Tezepelumab-ekko (Tezspire®) 7Thymic stromal lymphopoietinHypersensitivity; acute asthma and deteriorating disease;
reduction of corticosteroid
dosage; parasite infection; live
attenuated virus vaccines 7		Systemic: Pharyngitis; arthralgia; back pain 7
Tildrakizumab-asmn (Ilumetri®; Ilumya®)IL-23 p19Infections; prior evaluation for TB; hypersensensitivitySystemic: URTI; isr; diarrhea
Tocilizumab (Actemra®; RoActemra®)IL-6RBoxed warning: Serious
infections
Other: GI perforation; avoid
live vaccines; hypersensitivity;
laboratory monitoring		Systemic: Nasophraryngitis;
nausea; ↑ liver enzymes; IR; hypertension; thrombocytopenia; neutropenia; headache
Cutaneous: Dermatologic
reactions
Tralokinumab (Adtralza®)IL-13Hypersensitivity; conjunctivitis; helminth infection; avoid live and live attenuated vaccinesSystemic: URTI; conjunctivitis; eosinophilia; isr
Ustekinumab (Stelara®)IL-12
IL-23		Infections; tuberculosis; RPLS; malignancies; anaphylaxis; avoid live vaccinesSystemic: Nasopharyngitis; headache; dental infections; URTI; isr; arthralgia; GI
Cutaneous: Pruritus
Vedolizumab (Entyvio®)α4β7 integrinHypersensitivity/IR; infections; PML; liver injurySystemic: Headache; arthralgia; nausea; pyrexia; URTI; cough; bronchitis; influenza; back pain; pain in extremities;
nasopharyngitis
Cutaneous: Rash; pruritus
ACE2—angiotensin-converting enzyme 2; AHUS—atypical hemolytic uremic syndrome; ANGPTL3—angiopoietin-like 3; BLyS—B lymphocyte stimulator, also known as B cell-activating factor, BAFF; C5—complement component 5; CAPS—cryopyrin-associated periodic syndrome; CD—Crohn’s disease; CIU—chronic idiopathic urticaria; COVID—Coronavirus disease; CSs—corticosteroids; CV—cardiovascular; EBOV—Zaire ebolavirus; EM—erythema multiforme; GI—gastrointestinal; GP1—glycoprotein 1 of EBOV; HSTC—hematopoietic stem cell transplantation; IBD—inflammatory bowel disease; IFNAR—subunit I type I interferon receptor; IGF-1R—insulin-like growth factor receptor-1; ILD—interstitial lung disease; IR—infusion reaction; IRIS—immune reconstitution inflammatory syndrome; isr—injection site reaction; MAS—macrophage activation syndrome; MS—multiple sclerosis; NS—nervous system; PA—protective antigen of B. anthracis toxin; PCSK9—proprotein convertase subtilisin/kexin type 9; PML—progressive multifocal leukoencephalopathy; PNH—paroxysmal nocturnal hemoglobinuria; RANKL—receptor activator of nuclear factor kappa-B ligand (CD254); RBD—receptor binding domain; REMS—Risk Evaluation Mitigation Strategy; RSVF—human respiratory syncytial virus (F protein coat antigen); SARS-CoV-2—severe acute respiratory syndrome coronavirus 2; SJIA—active systemic juvenile idiopathic arthritis; SJS—Stevens–Johnson syndrome; URTI—upper respiratory tract infection; UTI—urinary tract infection; VEGF-A—vascular endothelial growth factor A. 1 Approved by the FDA or EMA or both. 2 Monoclonal antibodies are listed in alphabetical order. 3 Specificity of antibody. 4 Adverse events in addition to those mentioned as occurring, or potentially likely to occur, and shown in column 3. 5 Approved by the FDA on 17 December 2021. For safety data and adverse events, see Howard, J.F; Bril, V.; Vu, T.; et al. [21]. 6 Note added in press: Approved by the EMA on 17 December 2021. 7 Approved by the FDA on 17 December 2021. For safety data and adverse events, see Menzies-Gow, A.; Colice G, Griffiths, J.M.; et al. [22] and Menzies-Gow, A.; Corren, J.; Bourdin, A.; et al. [23]. ↑ increase.
Table
Table 5. Adverse events associated with approved 1 monoclonal antibodies used for cancer therapy (as at December 2021).
Table 5. Adverse events associated with approved 1 monoclonal antibodies used for cancer therapy (as at December 2021).
Monoclonal Antibody 2 INN and Trade NamesTarget 3Warnings, Precautions, Risks, and Safety ConcernsOther Adverse Events 4: Serious and Common
Ado-trastuzumab emtansine (Kadcyla®)HER2Boxed warning: Hepatotoxicity; cardiac toxicity; embryo-fetal toxicity
Other: IR; pulmonary toxicity;
extravasation; hemorrhage;
thrombocytopenia; neurotoxicity		Systemic: Pulmonary events; fetal harm; LVD; hypersensitivity/IR; nausea; fatigue; anemia; headache; musculoskeletal pain; increased
transaminases; constipation
Cutaneous: Rash; pruritus
Alemtuzumab
(Campath®; MabCampath®)		CD52Boxed warning: Cytopenias; IR;
immunosuppression/infections
Other: Immunization		Systemic: Pulmonary events; immunogenicity; cardiac events; diarrhea; nausea; emesis;
insomnia
Cutaneous: Rash; urticaria; erythema; pruritus
Amivantamab-vmjw
(Rybrevant®)		EGFR and c-MET receptorsILD/pneumonitis; IR; dermatologic (including acneiform dermatitis and TEN); ocular toxicity; embryo-fetal toxicitySystemic: IR; paronychia; musculoskeletal pain; dyspnea; nausea; fatigue; edema;
stomatitis; cough; constipation; vomiting
Cutaneous: Rash
Atezolizumab
(Tecentriq®)		PD-L1Immune-mediated pneumonitis,
colitis, hepatitis, endocrinopathies
(hypophysitis, thyroid disorders,
adrenal insufficiency, diabetes
mellitus); embryo-fetal toxicity		Systemic: IR; fatigue; nausea; infections;
urinary tract infections; decreased appetite;
diarrhea; pyrexia; constipation; dyspnea.
Cutaneous: Rash; pruritus
Avelumab
(Bavencio®)		PD-L1Immune-mediated pneumonitis,
colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction; IR		Systemic: Fatigue; musculoskeletal pain;
diarrhea; nausea; decreased appetite;
peripheral edema; urinary tract infection
Cutaneous: Rash; pruritus
Belantamab
mafodoton-blmf (Blenrep®)		BCMA with MMAF
microtubule inhibitor		Boxed warning: Ocular toxicity
Other: Thrombocytopenia; IR;
embryo-fetal toxicity		Systemic: Keratopathy; decreased visual
acuity, nausea; blurred vision; pyrexia; IR;
fatigue; decreased platelets, lymphocytes,
hemoglobin; increased creatinine, GGT
Bevacizumab
(Avastin®)		VEGF-ABoxed warning: GI perforation; surgery/wound healing; hemorrhage
Other: Non-GI fistula; RPLS; IR; CHF; hypertension; arterial/venous thromboembolism; eye disorders; proteinurea; neutropenia/infections; ONJ		Systemic: Pulmonary events; epistaxis; headache; rectal hemorrhage; dry skin; necrotizing fasciitis; taste alteration; lacrimation disorder; ovarian failure
Cutaneous: Exfoliative dermatitis; alopecia
Blinatumomab (Blincyto®)CD19/CD3 epsilonBoxed warning: CRS; neurological
toxicities Other: Infections;
neutropenia and febrile neutropenia; TLS; elevated liver enzymes;
leukoencephalopathy 		Systemic: HLH; pyrexia; lymphopenia; leukopenia; chills; headache; CNS symptoms
(disorientation, confusion, tremor, speech
disorders); hypokalemia; pneumonia; sepsis,
constipation, peripheral edema
Cutaneous: Rash
Brentuximab vedotin(Adcetris®)CD-30Boxed warning: PML
Other: Peripheral neuropathy; IR and anaphylaxis; neutropenia; infections; fetal harm; hepatotoxicity; TLS; SJS		Systemic: Cytopenias; immunogenicity; URTI; pyrexia; nausea; vomiting; fatigue; cough;
anaphylaxis
Cutaneous: Rash; pruritus; SJS; alopecia
Catumaxomab
(Removab®)		EpCAM/CD3Monitor and evaluate for: CRS; SIRS; HAMA/HARA; GI hemorrhage;
hepatic disorders; abdominal
infection; ileus/intestinal perforation;
decreased lymphocyte count		Systemic: Cytopenias; hepatotoxicity;
abdominal disorders; pyrexia; chills; nausea;
vomiting; infections; immunogenicity;
dyspnea
Cutaneous: Rash; erythema; allergic dermatitis;
hyperhidrosis; pruritus
Cemiplimab-rwlc
(Libtayo®)		PD-1Immune-mediated pneumonitis,
colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions; IR; embryo-fetal toxicity		Systemic: Diarrhea; fatigue; nausea;
constipation; musculoskeletal pain
Cutaneous: Rash; pruritus
Cetuximab
(Erbitux®)		EFGRBoxed warning: Serious IR and
cardiopulmonary arrest.
Other: Pulmonary toxicity; dermatologic toxicity; hypomagnesemia		Systemic: Electrolyte imbalance; infection; GI; anaphylaxis; headache; diarrhea
Cutaneous: Acneiform rash; nail changes; xeroderma; paronychial inflammation; pruritus
Daratumumab
(Darzalex®)		CD38IR; interference with serological
testing; neutropenia;
thrombocytopenia		Systemic: Neutropenia; thrombocytopenia;
fatigue; nausea; diarrhea; constipation;
vomiting; muscle spasms; arthralgia; back pain; pyrexia; chills; dizziness; insomnia; cough; dyspnea; peripheral edema; peripheral
sensory neuropathy; URTI
Denosumab (Prolia®; Xgeva®)RANKLHypocalcemia; ONJ; embryo-fetal toxicitySystemic: Osteomyelitis; hypophosphatemia; dyspnea; fatigue/asthenia; back pain; nausea; extremity pain
Cutaneous: Rash; pruritus; dermatitis; eczema
Dinutuximab
(Unituxin®)		GD2Boxed warning: Serious IR;
neuropathy
Other: CLS and hypotension; infection; RPLS; neurological disorders of eye; BMS; electrolyte abnormalities; AHUS; embryo-fetal toxicity		Systemic: Hypokalemia; pain; fever;
hypocalcemia; hyponatremia; anemia;
thrombocytopenia; lymphopenia;
neutropenia; increased AST, ALT; GI
Cutaneous: Urticaria
Dostarlimab-gxly (Jemperli®)PD-1Immune-mediated colitis, pneumonitis, hepatitis, endocrinopathies,
nephritis, dermatologic adverse
reactions; IR; complications of allogeneic HSCT after PD-1/L-1–blocking
antibody; embryo-fetal toxicity		Systemic: Fatigue/asthenia; nausea; diarrhea; anemia
Durvalumab
(Imfinzi®)		PD-L1Immune-mediated pneumonitis,
colitis, hepatitis, nephritis,
endocrinopathies; dermatologic
reactions; embryo-fetal toxicity;
infections; IR		Systemic: Fatigue; musculoskeletal pain;
diarrhea; nausea; decreased appetite;
peripheral edema; urinary tract infection; pneumonitis; dyspnea; URTI; cough
Cutaneous: Rash; pruritus
Elotuzumab
(Empliciti®)		SLAMF7IR; infections; second primary malignancies; hepatotoxicity; interference in monitoring M-protein impacting determination of complete response in patients with IgGκ myeloma
protein 		Systemic: Fatigue; diarrhea; pyrexia; constipation; cough; peripheral neuropathy;
nasopharyngitis; URTI; decreased appetite; pneumonia
Enfortumab-vedotin-ejfv
(Padcev®)		Nectin-4 with MMAE
microtubule inhibitor		Hyperglycemia; peripheral
neuropathy; ocular disorders; skin reactions; infusion site extravasation; embryo-fetal toxicity		Systemic: Fatigue; peripheral neuropathy;
decreased appetite; rash; alopecia; nausea;
dysgeusia; diarrhea; dry eye
Cutaneous: Pruritus; dry skin
Fam-trastuzumab deruxtecan-nxki
(Enhertu®)		HER2Boxed warning: ILD and pneumonitis; embryo-fetal toxicity
Other: Neutropenia; LVD		Systemic: Decreased hemoglobin, white blood cells, neutrophils, lymphocytes, platelets;
nausea; vomiting; constipation; fatigue;
decreased appetite; anemia; diarrhea;
hypokalemia; pyrexia; alopecia; increased blood bilirubin, aspartate aminotransferase, AP, alanine aminotransferase
Gemtuzumab ozogamicin
(Mylotarg®)		CD33Boxed warning: Hepatotoxicity
including severe or fatal hepatic
veno-occlusive disease
Other: IR including anaphylaxis;
hemorrhage; embryo-fetal toxicity		Systemic: Hemorrhage; infection; fever;
nausea; vomiting; constipation; headache;
increased ALT, AST; mucositis
Cutaneous: Rash
Ibritumomab tiuxetan (Zevalin®)CD20Boxed warning: Serious IR; severe
cytopenias; severe mucocutaneous and cutaneous reactions
Other: MDS and AML; extravasation; immunization 		Systemic: Infections; asthenia; musculoskeletal symptoms; GI; hemorrhage; hypersensitivity
Cutaneous: Exfoliative dermatitis; bullous
dermatitis; EM; SJS; TEN
Inotuzumab ozogamicin
(Besponsa®)		CD22Boxed warning: Hepatotoxicity
including hepatic veno-occlusive
disease; increased risk of post-
transplant non-relapse mortality
Other: myelosuppression; embryo-
fetal toxicity; QT interval prolongation		Systemic: IR; cytopenias; nausea; fatigue; hemorrhage; pyrexia; infection; headache; febrile neutropenia; increased transaminases;
hyperbilirubinemia
Ipilimumab
(Yervoy®)		CTLA-4Boxed warning: Immune-mediated
adverse reactions		Systemic: Diarrhea; fatigue; colitis
Cutaneous: Rash; pruritus; dermatitis
Isatuximab-irfc
(Sarclisa®)		CD38IR; neutropenia; second primary
malignancies; indirect antiglobulin test and interference with serum electrophoresis and immunofixation tests		Systemic: Neutropenia; IR; pneumonia; URTI; diarrhea; anemia; lymphopenia;
thrombocytopenia
Loncastumab tesirine-lpyl
(Zynlonta®)		CD19 with teserine cytotoxic agentEffusions (pericardial, pleural,
ascites); embryo-fetal toxicity;
myelosuppression; infections;
cutaneous reactions (including
photosensitivity)		Systemic: Thrombocytopenia; increased gamma-glutamyltransferase; neutropenia; nausea; anemia; hyperglycemia; transaminase elevation; fatigue; hypoalbuminemia; edema; musculoskeletal pain
Cutaneous: Rash
Margetuximab-cmkb
(Margenza®)		HER2Boxed warning: LVD; embryo-fetal
toxicity		Systemic: Fatigue/asthenia; nausea; diarrhea; vomiting; constipation; IR; headache; pyrexia; alopecia; abdominal pain; peripheral neuropathy; arthralgia/myalgia; cough; decreased
appetite; dyspnea; extremity pain
Cutaneous: PPE
Mogamulizumab-kpkc (Poteligeo®)CCR4Dermatologic toxicity; IR; infections; autoimmune reactions; HSCT
complications 		Systemic: IR; diarrhea; fatigue; URTI;
musculoskeletal pain
Cutaneous: Rash
Moxetumomab pasudox-
tdfk (Lumoxiti®)		CD22Boxed warning: CLS; hemolytic uremic syndrome
Other: Renal toxicity;
electrolyte abnormalities; IR		Systemic: Edema; nausea; fatigue; headache; pyrexia; constipation; diarrhea; anemia;
increased creatinine, ALT, AST; hypophosphatemia; hypocalcemia
Naxitamab-gqgk
(Danyelza®)		GD2Boxed warning: Serious IR;
neurotoxicity including RPLS		Systemic: IR; isr; pain; tachycardia; vomiting; cough; nausea; diarrhea; decreased appetite; hypertension; fatigue; peripheral neuropathy; edema; urticaria; pyrexia; headache; anxiety; irritability; decreased lymphocytes; neutrophils, hemoglobin, platelets, K, Ca, Na,
glucose, albumin, phosphate; increased
alanine aminotransferase
Cutaneous: EM
Necitumumab
(Portrazza®)		EGFRBoxed warning: Cardiopulmonary arrest; hypo-magnesemia
Other: Venous, arterial thromboembolic events; dermatologic toxicities; embryo-fetal toxicity; ↑ toxicity, mortality in patients with non-
squamous NSCLC; IR		Systemic: Diarrhea; vomiting
Cutaneous: Rash; dermatitis acneiform
Nivolumab
(OPDIVO®)		PD-1Immune-mediated adverse reactions; embryo-fetal toxicitySystemic: Increased ALT, AST, AP; hyponatremia; hyper- and hypokalemia; hyper- and hypocalcemia; lymphopenia; fatigue;
asthenia; musculoskeletal and abdominal pain; dyspnea; cough; GI.
Cutaneous: Rash; pruritus
Obinutuzumab (Gazyva®; Gazyvaro®)CD20Boxed warning: Hepatitis B virus
reactivation; PML.
Other: IR; TLS;
neutropenia; thrombocytopeia;
infections; immunization 		Systemic: Anemia; pyrexia; musculoskeletal disorders; headache; cough
Ofatumumab (Arzerra®)CD20IR; Hepatitis B virus reactivation; PML; cytopenias intestinal
obstruction; immunization		Systemic: Infections; pneumonia; neutropenia; pyrexia; dyspnea; cough; diarrhea; URTI;
nausea; fatigue; bronchitis
Cutaneous: Rash; urticaria; hyperhidrosis.
Olaratumab (Lartruvo®)PDGFR-αIR; embryo-fetal toxicitySystemic: Olaratumab + doxorubicin: fatigue; musculoskeletal pain; diarrhea; decreased
appetite; headache; neuropathy; cytopenias; hyperglycemia; elevated aPTT; hypokalemia; hypophosphatemia
Cutaneous: Alopecia
Panitumumab
(Vectibix®)		EGFRBoxed warning: Dermatologic toxicity; IR
Other: Increased toxicity with
bevacizumab and chemotherapy;
pulmonary toxicities; electrolyte
depletion; ocular events		Systemic: Pulmonary events; pulmonary
embolism; GI; fatigue; abdominal pain;
hypomagnesemia
Cutaneous: Rash; dermatitis ‘acneiform’;
erythema; exfoliation; paronychia; skin
fissures; photosensitivity; xerosis; pruritus
Pembrolizumab (Keytruda®)PD-1Immune-mediated adverse reactions; embryo-fetal toxicitySystemic: Fatigue; peripheral edema; chills;
pyrexia; renal failure; cellulitis; decreased
appetite; dyspnea; arthralgia; nausea;
diarrhea; cough
Cutaneous: Rash; pruritus; vitiligo
Pertuzumab
(Perjeta®)		HER2Boxed warning: Cardiomyopathy;
embryo-fetal toxicity.
Other: IR; hypersensitivity/anaphylaxis		Systemic: Neutropenias; LVD; peripheral
neuropathy; fatigue; GI; asthenia
Cutaneous: Rash; paronychia; pruritus;
alopecia; PPE (in combination therapy)
Polatuzumab vedotin-piiq (Polivy®)CD79bPeripheral neuropathy; myelosuppression and related reactions;
infections; IR; TLS; PML; hepatotoxicity; embryo-fetal toxicity		Systemic: Cytopenia; fatigue; decreased
appetite; diarrhea; pyrexia; pneumonia
Ramucirumab
(Cyramza®)		VEGFR2Boxed warning: Hemorrhage; GI
perforation; impaired wound
healing.
Other: A rterial thromboembolic events; IR; RPLS; hypertension;
deterioration in patients with
cirrhosis; proteinuria including
nephrotic syndrome; thyroid
dysfunction; embryo-fetal risk		Systemic: Hypertension; diarrhea; headache; hytremia; neutropenia; epistaxis; stomatitis; immunogenicity
Rituximab (Rituxan®; MabThera®)CD20Boxed warning: Fatal IRs; TLS;
potentially fatal PML and severe
mucocutaneous reactions
Other: hepatitis B virus reactivation;
infections; cardiac arrhythmias; bowel obstruction and perforation		Systemic: Pulmonary events; renal toxicity; neutropenias; serum sickness; anaphylaxis;
fever; lymphopenia; chills; asthenia
Cutaneous: Paraneoplastic pemphigus;
lichenoid dermatitis; vesicullobullous
dermatitis; SJS; TEN
Sacituzumab
govitecan-hziy (Trodelvy®)		Trop-2 with topoisomerase
inhibitor		Boxed warning: Severe neutropenia; severe diarrhea
Other: Hypersensitivity; nausea/vomiting; risk of neutropenia increased in individuals with reduced uridine diphosphate-glucuronosyl transferase 1A1; embryo-fetal toxicity		Systemic: Nausea; neutropenia; diarrhea;
fatigue; anemia; vomiting; alopecia;
constipation; decreased appetite; abdominal pain
Cutaneous: Rash
Siltuximab
(Sylvant®)		IL-6Not for patients with severe
infections or live vaccines; IR;
cautionary use in patients with GI perforation risk		Systemic: Hyperuricemia; URTI; increased weight
Cutaneous: Rash; pruritus
Tafasitamab-cxix
(Monjuvi®)		D19IR; myelosuppression; infections;
embryo-fetal toxicity		Systemic: Neutropenia; fatigue; anemia;
diarrhea; thrombocytopenia; cough; pyrexia;
peripheral edema; URTI; decreased appetite
Tisotumab vedotin-tftv
(Tivdak®)		TF with MMAE microtubule inhibitorBoxed warning: Ocular toxicity
Other: Ocular adverse reactions, e.g., conjunctival reactions, dry eyes,
corneal reactions, blepharitis;
ulcerative keratitis; peripheral
neuropathy; pneumonitis; embryo-
fetal toxicity 		Systemic: Most serious: ileus; hemorrhage; pneumonia; sepsis; pyrexia; peripheral
neuropathy; constipation. Most common:
diarrhea; peripheral neuropathy; conjunctival and corneal reactions; fatigue; alopecia;
epistaxis; decreased hemoglobin, lymphocytes, and leukocytes; increased creatinine; dry eye; prothrombin international
normalized ratio; aPTT prolonged
Cutaneous: Rash
Trastuzumab
(Herceptin®)		HER2Boxed warning: Cardiomyopathy; IR; pulmonary toxicity
Other: Exacerbation of chemotherapy-induced neutropenia; embryo-fetal
toxicity		Systemic: Neutropenia; anemia; thrombocytopenia; pulmonary events; LVD; GI; chills;
fever; URTI; anaphylaxis/angioedema;
headache; cough; stomatitis; mucosal
inflammation
Cutaneous: Rash; nail disorders; pruritus
AHUS—atypical hemolytic syndrome; ALT—alanine transaminase; AML—acute myelogenous leukemia; AP—alkaline phosphatase; aPTT—activated partial thromboplastin time; AST—aspartate transaminase; BCMA—B cell maturation antigen; BMS—bone marrow suppression; CHF—congestive heart failure; CLS—capillary leak syndrome; c-MET—mesenchymal-epithelial transition factor, a tyrosine kinase receptor; CNS—central nervous system; CRS—cytokine release syndrome; CTLA-4—cytotoxic T lymphocyte-associated antigen 4; DLBCL—diffuse large B cell lymphoma; EGFR—epidermal growth factor receptor (HER1, ErbB-1); EM—erythema multiforme; EpCAM—epithelial cell adhesion molecule; GD2—disialoganglioside expressed on tumors of neuroectodermal origin; GGT—gamma-glutamyl transferase; GI—gastrointestine/gastrointestinal symptoms, e.g., nausea, diarrhea, vomiting, constipation; GM-CSF—granulocyte-macrophage colony-stimulating factor; HAMA—human antimouse antibody; HARA—human antirat antibody; HER2—human epidermal growth factor 2, also known as Neu, ErbB2, CD340, or p185; HLH—hemophagocytic lymphohistiocytosis; IR—infusion reactions; isr—injection site reaction; ILD—interstitial lung disease; LBCL—large B cell lymphoma; LVD—left ventricular dysfunction; MMAE—monomethyl auristatin E; MMAF—monomethyl auristatin F; MDS—myelodysplastic syndrome; mTNBC—metastatic triple-negative breast cancer; ONJ—osteonecrosis of the jaw; PD-1—programmed cell death protein 1; PD-L1; PDGFRA—platelet-derived growth factor receptor A; PML—progressive multifocal leucoencephalopathy; PPE—palmar plantar erythrodysaesthesia; RANKL—receptor activator of nuclear factor kappa-B ligand (CD254); RPLS—reversible posterior leukoencephalopathy syndrome; SIRS—systemic inflammatory response syndrome; SJS—Stevens–Johnson syndrome; TEN—toxic epidermal necrolysis; teserine—also known as SG3249, a pyrrolobenzodiazepine dimer; TF—tissue factor, platelet tissue factor, factor III, CD142; TLS—tumor lysis syndrome; Trop-2—trophoblast cell surface antigen-2; URTI—upper respiratory tract infection; VEGF—vascular endothelial growth factor; VEGFR-2—vascular endothelial growth factor receptor 2. 1 Approved by the FDA or EMA or both. 2 Monoclonal antibodies are listed in alphabetical order. 3 Specificity of antibody. 4 Adverse events in addition to those mentioned as warnings and precautions in column 3. ↑ increase.
Table
Table 6. Individual approved monoclonal antibodies associated with adverse events affecting different organs and tissues.
Table 6. Individual approved monoclonal antibodies associated with adverse events affecting different organs and tissues.
Anaphylaxis 1Infusion ReactionsCytopeniasPulmonary Adverse
Events 2		Cardiac
Adverse
Events		Hepatotoxicity 2Other Immune-
Mediated
Reactions 3		Embryo-Fetal ToxicityDermatologic
Toxicity 3
Monoclonal
Antibodies for
non-cancer
therapy
Adalimumab
Belimumab
Casirivimab+
Imdevimab 4
Certolizumab pegol
Evinacumab-dgnb
Infliximab
Obiltoxaximab
Omalizumab
Palivisumab
Regdanvirimab
Reslizumab
Tocilizumab
Ustekinumab		Alemtuzumab 5
Anifrolumab-fnia
Ansuvimab-zykl
Atoltivimab 6
Belimumab
Casirivimab+
Imdevimab 4
Crizanlizumab-tmca
Emapalumab-lzsg
Inebilizumab-cdon
Infliximab
Obiltoxaximab
Ocrelizumab
Raxibacumab
Regdanvirimab
Sotrovimab
Teprotumumab-trbw
Tocilizumab
Vedolizumab		Abciximab
Adalimumab
Alemtuzumab 5
Brodalumab
Certolizumab pegol
Infliximab
Palivisumab
Sarilumab
Satralizumab-mwge
Tocilizumab		Adalimumab
Alemtuzumab 5
Golimumab
Infliximab		Adalimumab
Bezlotoxumab
Certolizumab pegol
Golimumab
Romosozumab-aqqg		Adalimumab
Certolizumab pegol
Daclizumab
Evolocumab
Infliximab
Natalizumab
Vedolizumab		Adalimumab
Alemtuzumab
Alirocumab
Daclizumab
Infliximab
Omalizumab		Evinacumab-dgnb
Inebilizumab-cdon		Abciximab
Adalimumab
Alemtuzumab 5
Alirocumab
Bimekizumab
Certolizumab pegol
Daclizumab
Denosumab 7
Evolocumab
Golimumab
Infliximab
Natalizumab
Obiltoxaximab
Ocrelizumab
Omalizumab
Raxibacumab
Secukinumab
Tocilizumab
Monoclonal
Antibodies for
cancer therapy
Brentuximab vedotin
Cetuximab
Gemtuzumab ozogamicin
Pertuzumab
Rituximab
Trastuzumab		Ado-trastuzumab
Alemtuzumab 8
Amivantamab-vmjw
Atezolizumab
Avelumab
Belantamab mafodoton-blmf
Bevacizumab
Brentuximab vedotin
Cemiplimab-rwlc
Cetuximab
Daratumumab
Dinutuximab
Dostarlimab-gxly
Durvalumab
Elotuzumab
Gemtuzumab ozogamicin
Ibritumomab
tiuxetan
Inotuzumab
ozogamicin
Isatuximab-irfc
Mogamulizumab-kpkc
Moxetumomab
pasudox-tdfk
Naxitamab-gqgk
Necitumumab
Obinutuzumab
Ofatumumab
Olaratumab
Panitumumab
Pertuzumab
Polatuzumab
vedotin-piiq
Ramucirumab
Rituximab
Siltuximab
Tafasitamab-cxix
Trastuzumab		Ado-trastuzumab
Alemtuzumab 8
Belantamab mafodoton-blmf
Blinatumomab
Brentuximab vedotin
Catumaxomab
Daratumumab
Dinutuximab
Fam-trastuzumab
deruxtecan-nxki
Ibritumomab
tiuxetan
Inotuzumab
ozogamicin
Isatuximab-irfc
Loncastumab-tesirine-lpyl
Naxitamab-gqgk
Obinutuzumab
Ofatumumab
Olaratumab
Pertuzumab
Polatuzumab vedotin-piiq
Ramucirumab
Rituximab
Sacituzumab
govetican-hziy
Tafasitamab-cxix
Tisotumab
vedotin-tftv
Trastuzumab		Ado-trastuzumab
Alemtuzumab 8
Amivantamab-vmjw
Atezolizumab
Avelumab
Bevacizumab
Cemiplimab-rwlc
Cetuximab
Dostarlimab-gxly
Durvalumab
Fam-trastuzumab
deruxtecan-nxki
Ipilimumab
Nivolumab
Panitumumab
Pembrolizumab
Rituximab
Tisotumab
vedotin-tftv
Trastuzumab		Ado-trastuzumab
Alemtuzumab 8
Bevacizumab
Cetuximab
Fam-trastuzumab
deruxtecan-nxki
Ibritumomab tiuxetan
Inotuzumab ozogamicin
Margetuximab-cmkb
Necitumumab
Obinutuzumab
Pertuzumab
Ramucirumab
Rituximab
Romosozumab-aqqg
Trastuzumab		Ado-trastuzumab
Atezolizumab
Avelumab
Brentuximab vedotin
Catumaxomab
Cemiplimab-rwlc
Dostarlimab-gxly
Durvalumab
Elotuzumab
Gemtuzumab ozogamicin
Inotuzumab
Ozogamicin
Obinutuzumab
Ofatumumab
Polatuzumab vedotin-piiq
Rituximab		Atezolizumab
Avelumab
Cemiplimab-rwlc
Dostarlimab-gxly
Durvalumab
Ipilimumab
Mogamulizumab-kpkc
Nivolumab
Pembrolizumab		Amivantamab-vmjw
Atezolizumab
Belantamab
mafodoton-blmf
Cemiplimab-rwlc
Denosumab 9
Dinutuximab
Dostarlimab-gxly
Durvalumab
Enfortumab vedotin-ejfv
Fam-trastuzumab
Gemtuzumab
ozogamicin
Inotuzumab
ozogamicin
Loncastumab
tesirine-lpyl
Margetuximab-cmkb
Necitumumab
Nivolumab
Olaratumab
Pembrolizumab
Pertuzumab
Polatuzumab vedotin-piiq
Ramucirumab
Sacituzumab
govetican-hziy
Tafasitamab-cxix
Tisotumab
vedotin-tftv
Trastuzumab		Alemtuzumab 8
Amivantamab-vmjw
Bevacizumab
Brentuximab vedotin
Catumaxomab
Cemiplimab-rwlc
Cetuximab
Denosumab 9
Dostarlimab-gxly
Durvalumab
Enfortumab
vedotin-ejfv
Ibritumomab tiuxetan
Ipilimumab
Loncastumabtesirine-lpyl
Margetuximab-cmkb
Mogamulizumab-kpkc
Naxitamab-gqgk
Necitumumab
Panitumumab
Pembrolizumab
Pertuzumab
Rituximab
Trastuzumab
For infusion reactions, cytopenias, pulmonary events, and dermatologic toxicity, alemtuzumab as Lemtrada® and Campath® are counted as one mAb not two; likewise, denosumab as Prolia® and Xgeva® are counted as one mAb in inducing dermatologic toxicity. 1 A type I immediate hypersensitivity. 2 Includes some mAb-induced hypersensitivities. 3 mAbs including, and in addition to, those clearly identified as inducing an adverse event via a type I, II, III, or IV hypersensitivity mechanism. 4 A combination of two mAbs directed to the spike protein receptor binding domain of SARS-CoV-2. 5 As Lemtrada®. 6 A combination of Zaire ebolavirus glycoprotein-1-directed human monoclonal antibodies (atoltivimab, maftivimab, and odesivimab), indicated for the treatment of infection caused by Zaire ebolavirus. 7 As Prolia®. 8 As Campath®. 9 As Xgeva®.
Table
Table 7. Approved monoclonal antibodies subject to FDA warnings and precautions for cytopenias.
Table 7. Approved monoclonal antibodies subject to FDA warnings and precautions for cytopenias.
CytopeniaThrombocytopeniaNeutropeniaLymphocytopenia
AdalimumabAbciximabBevacizumabCatumaxomab
Alemtuzumab 1Ado-trastazumab
emtansine		Blinatumomab
Certolizumab pegolBelantamab mafodoton-blmfBrentuximab vedotin
Ibritumomab tiuxetan 1DaratumumabDaratumumab
InfliximabPalivisumabFam-trastuzumab
Deruxtecan-nxki
OfatumumabSarilumabIsatuximab-irfc
Obinutuzumab
Sacituzumab govitecan-hziy 1
Sarilumab
Satralizumab-mwge
Trastuzumab
1 Subject to boxed warning.
Table
Table 8. Cardiac adverse events caused by approved monoclonal antibodies used for therapy.
Table 8. Cardiac adverse events caused by approved monoclonal antibodies used for therapy.
Monoclonal AntibodyCardiac Adverse Events
Adalimumab.Heart failure
Ado-trastuzumab emtansine 1 Decreased LVEF
AlemtuzumabCardiomyopathy, decreased LVEF, cardiac arrhythmias associated with infusions
Bevacizumab CHF: incidence of grade 3 reaction for LVD 1%
BezlotoxumabHeart failure
Brentuximab vedotinSupraventricular arrhythmia in systemic anaplastic large cell lymphoma
Certolizumab pegolHeart failure
Cetuximab Cardiopulmonary arrest/sudden death
Fam-trastuzumab deruxtecan-nxkiLVD
GolimumabHeart failure
Ibritumomab tiuxetanCardiac arrest related to infusions
Inotuzumab ozogamicinQT interval prolongation
Margetuximab-cmkb 1LVD
Necitumumab 1Cardiopulmonary arrest
Obinutuzumab Worsening of preexisting cardiac conditions leading to fatal cardiac events
Pertuzumab 1 Cardiomyopathy manifesting as CHF and decreased LVEF
Ramucirumab Serious, sometimes fatal, myocardial infarction
Rituximab Cardiac arrhythmias and angina, fatal cardiac failure
Romosozumab-aqqg 1Myocardial infarction, cardiac events, cardiovascular death
Trastuzumab 1Cardiomyopathy manifesting as CHF and decreased LVEF
CHF—congestive heart failure; LVD—left ventricular dysfunction; LVEF—left ventricular ejection fraction. 1 FDA boxed warnings apply.
Table
Table 9. Liver adverse events induced by approved monoclonal antibodies used for therapy.
Table 9. Liver adverse events induced by approved monoclonal antibodies used for therapy.
Monoclonal AntibodyLiver Adverse Events
AdalimumabReactivates hepatitis B; liver failure
Ado-trastuzumabHepatotoxicity
AtezolizumabImmune-mediated hepatitis
AvelumabImmune-mediated hepatitis
Brentuximab vedotinHepatotoxicity
CatumaxomabHepatic disorders—hepatotoxicity
Cemiplimab-rwlcImmune-mediated hepatitis
Certolizumab pegolReactivates hepatitis B
DaclizumabHepatic injury including autoimmune hepatitis
Dostarlimab-gxlyImmune-mediated hepatitis
DurvalumabImmune-mediated hepatitis
ElotuzumabHepatotoxicity
EvolocumabHepatic impairment
Gemtuzumab ozogamicinHepatotoxicity including severe or fatal hepatic veno-occlusive disease
GolimumabReactivates hepatitis B
InfliximabHepatotoxicity
Inotuzumab ozogamicinHepatotoxicity including severe or fatal hepatic veno-occlusive disease
NatalizumabHepatotoxicity
ObinutuzumabReactivates hepatitis B
OfatumumabReactivates hepatitis B
Polatuzumab vedotin-piiqHepatotoxicity
RituximabReactivates hepatitis B
VedolizumabPossibility of liver injury suggested by elevated levels of transaminase and/or bilirubin
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Baldo, B.A. Immune- and Non-Immune-Mediated Adverse Effects of Monoclonal Antibody Therapy: A Survey of 110 Approved Antibodies. Antibodies 2022, 11, 17. https://doi.org/10.3390/antib11010017

AMA Style

Baldo BA. Immune- and Non-Immune-Mediated Adverse Effects of Monoclonal Antibody Therapy: A Survey of 110 Approved Antibodies. Antibodies. 2022; 11(1):17. https://doi.org/10.3390/antib11010017

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Baldo, Brian A. 2022. "Immune- and Non-Immune-Mediated Adverse Effects of Monoclonal Antibody Therapy: A Survey of 110 Approved Antibodies" Antibodies 11, no. 1: 17. https://doi.org/10.3390/antib11010017

APA Style

Baldo, B. A. (2022). Immune- and Non-Immune-Mediated Adverse Effects of Monoclonal Antibody Therapy: A Survey of 110 Approved Antibodies. Antibodies, 11(1), 17. https://doi.org/10.3390/antib11010017

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