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

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.


Introduction
In the last decade, along with the continuing development of the disciplines of genomics, 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 inflammatorybased 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 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].

Monoclonal Antibody Targets and Indications
Of the 110 currently approved and registered mAbs (Tables 1 and 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 Tables 1 and 2 is 112 (66 for non-cancer and 46 for cancer therapies), alemtuzumab and denosumab each appear in both lists under different trade names.

Monoclonal Antibody Targets and Indications
Of the 110 currently approved and registered mAbs (Tables 1 and 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 Tables 1 and 2 is 112 (66 for non-cancer and 46 for cancer therapies), alemtuzumab and denosumab each appear in both lists under different trade names.      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.
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 (Tables 1 and 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 (Tables 2 and 3).

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. Tables 4 and 5 summarize adverse events associated with mAbs used for noncancer 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.

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 hy-persensitivities 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.

•
Type I 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 (Tables 4 and 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.  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 ® .
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 (Tables 5 and 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). 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 (Tables  5 and 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 (Tables 4-6, 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). 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 (Tables 4-6, 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).

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 Tables  4-6 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/). 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%).

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 Tables 4-6 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%). 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 (Tables 4 and 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 × 10 9 /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 (Tables 4-6). FDA boxed warnings have been issued for three mAbs, namely, for sacituzumab goveticanhziy-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 (Tables 4 and 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 Tables 4 and 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 (Tables 4-6 and 8) in a range of effects, including cardiomyopathy, myocardial infarction, cardiac arrhythmias, cardiopulmonary arrest, congestive heart failure, left ventricular 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 (Tables 4-6 and 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. Table 9. Liver adverse events induced by approved monoclonal antibodies used for therapy.

Monoclonal Antibody
Liver Adverse Events

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 × 10 9 /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,

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 × 10 9 /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 HLHlike 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).

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. 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.