key: cord-0059469-e185vlpw
authors: Baldo, Brian A.; Pham, Nghia H.
title: Targeted Drugs for Cancer Therapy: Small Molecules and Monoclonal Antibodies
date: 2020-12-09
journal: Drug Allergy
DOI: 10.1007/978-3-030-51740-3_14
sha: 2e4e4ae132289ae182b5b94ffdb3cbe6345625e1
doc_id: 59469
cord_uid: e185vlpw

Specific targeting of tumor cells without inflicting collateral damage on normal healthy cells has been, and remains, a long-standing aim in cancer therapy. Effective targeting of tumor cells without accompanying toxicity has started to be realized with the introduction of signal transduction therapies and monoclonal antibodies (mAbs). Small molecule examples of the former drugs include imatinib (which inhibits both the ABL and BCR-ABL tyrosine kinases); gefitinib and erlotinib; mTOR inhibitors; histone deacetylase inhibitors (HDACIs); all-trans retinoic acid (tRA) and arsenic trioxide that target PML; the synthetic retinoic X receptor agonist bexarotene for T cell lymphoma; some hormone therapies; and proteosome inhibitors including bortezomib and carfilzomib. For most of the tyrosine kinase inhibitors targeting EGFRs, papulopustular rash, hand-foot skin reaction, mucositis, and nail abnormalities are the main adverse events. Retinoic acid syndrome occurs in some patients treated with tRA and/or arsenic trioxide. mTOR inhibitors are associated with a considerable number of adverse events including interstitial lung disease. Myelosuppression is a frequent event with HDACIs, and bortezomib, a proteosome inhibitor, may cause gastrointestinal symptoms, thrombocytopenia, peripheral neuropathy, and adverse cutaneous reactions including Sweet’s syndrome. Of the 85 currently approved mAbs, 34 recognizing 21 different targets are indicated for the treatment of cancers. Seven mAbs are antibody-drug conjugates (ADCs) which effect cell killing by an attached bioactive payload of a potentially lethal toxin, drug, cytokine, or radionuclide. Immune checkpoint inhibitors target inhibitory pathways regulating signaling between T cells and antigen-presenting cells. mAbs may provoke type I immediate hypersensitivities (anaphylaxis, urticaria), types II (rituximab-induced neutropenia) and III hypersensitivities (serum sickness), delayed type IV cutaneous reactions, pulmonary toxicities, and cardiac adverse events. Skin reactions after cetuximab and panitumumab often appear as papulopustular eruptions. Severe infusion reactions provoked by mAbs can resemble anaphylaxis, cytokine-release syndrome (CRS), infusion, and type I allergic reactions, while tumor lysis syndrome, unlike CRS, is easy to distinguish from type I immediate reactions.

Specific targeting of tumor cells without inflicting collateral damage on normal healthy cells has been, and remains, a long-standing aim in cancer therapy. In attempts to destroy rapidly dividing malignant cells, the mainstay of therapy has been the administration of small cytotoxic molecules used with, or without, radiation therapy. This rather crude and non-discriminatory approach of killing rapidly dividing cells often adversely affects some normal, healthy cells such as mucosal lining cells and those in the bone marrow and hair follicles. Frequent consequences of this approach using agents demonstrating non-specific toxicity are patients with poor tolerance of the chemo-and radiation therapies, delays, interruptions or discontinuation of therapy, and sometimes poor survival outcomes.

Here, targeted drugs have been divided into the natural or synthetic "small" molecules (i.e., generally MW ≤ 1 kDa; often called "chemotherapy" drugs) and the biologics. Note that the macrolide mammalian (mechanistic) target of rapamycin (mTOR) inhibitors, sirolimus (also known as rapamycin), temsirolimus, and everolimus, have molecular weights of ~1000 Da. The small molecules are almost always of nonbiologic origin whereas the biologics in the main are particular monoclonal antibodies (mAbs) and a few recombinant fusion proteins, for example, aflibercept.

Effective targeting of tumor cells without accompanying toxicity has started to be realized with the introduction of signal transduction therapies and monoclonal antibodies (mAbs). The principle of signal transduction therapy is shown diagrammatically in Fig. 14.1. Signal transduction involves the utilization of biochemically induced signals generated by a range of large and small molecules such as growth factors, neurotransmitters, hormones, cytokines, chemokines, and ATP, to produce a wide variety of cell responses like cell division, metabolic changes, gene expression, and cell death. Signal transduction therapy then depends on identifying signaling proteins and their altered pathways. The first example of understanding and applying a signaling network to design and employ targeted drugs was the use of the estrogen receptor antagonist tamoxifen for the treatment of some estrogendependent breast cancers. The first signaling proteins to be utilized as targets for a new generation of unique anticancer drugs were protein kinases.

Kinases and phosphatases are enzymes that modulate activities of proteins in the cell. Kinases transfer a γ-phosphate group (PO 3 2− ) from adenosine triphosphate to the hydroxyl group of tyrosine on signal transduction molecules (proteins), thus maintaining cellular functions, while phosphatases remove phosphate groups reversing the actions. The reactants, products, and stoichiometric numbers for the protein kinase-catalyzed reaction is: Tyrosine kinases can be classified as receptor and non-receptor kinases. Approximately 538 kinases encoded in the human genome promote cell proliferation, survival, and migration, but overexpression, dysregulation, and mutations of protein kinases involve them in the pathogenesis of many diseases including an association with oncogenesis. As a consequence of genetic mutations and chromosome reshuffling, many human malignancies are now known to be associated with the actions and dysfunctions of protein and lipid kinases and malfunctioning phosphatases. According to Manning et al. (The protein kinase complement of the human genome. Science 2002;298:1912) , the human protein kinase super family consists of 518 enzymes, classified as 385 protein-serine/threonine kinases, 90 (58 receptor and 32 non-receptor) protein-tyrosine kinases, and 43 protein-tyrosine kinase-like enzymes. At March 2019, the US FDA had approved 48 small molecule protein kinase inhibitors directed against about 20 different protein kinases: 25 inhibitors of receptor protein-tyrosine kinases, 10 inhibitors of nonreceptor protein-tyrosine kinases, and 13 inhibitors of protein-serine/threonine tyrosine kinases. Forty-three of the 48 kinase inhibitors are directed toward malignancies (36 solid tumors, 7 non-solid tumors). Eighteen are multikinase inhibitors. 

The original targeting strategy for cancer therapies was based on the instability of the cancer genome compared to the normal cell. The Philadelphia translocation t(9;22)(q34;q11) or Philadelphia chromosome is a chromosomal defect resulting in gene fusion of the BCR and ABL genes. The BCR (breakpoint cluster region) gene is on chromosome 22 (region q11) and the ABL (so named because the Abelson leukemia virus has a similar protein) tyrosine kinase gene is on chromosome 9 (region q34). The resultant fusion gene is the BCR-ABL oncogene. The Philadelphia chromosome is a cytogenetic abnormality seen in 95% of chronic myeloid leukemia (CML) patients and 15-30% of adults with acute lymphoblastic leukemia (ALL) but absent from nonmalignant cells. Tyrosine kinases were implicated as oncogenes in some animal tumors induced by retroviruses more than 30 years ago. The oncogene BCR-ABL results in the expression of two forms of tyrosine kinases and a large increase in myeloid cell numbers. The BCR-ABL mutation is present in the great majority of CML patients, the Bcr-Abl fusion protein is unique to leukemic cells but absent from nonmalignant cells, it is expressed in high levels, and its tyrosine kinase activity is essential in the induction of leukemia. CML cells show absolute dependence ("oncogene addiction") on the kinase activity of protein Bcr-Abl, and this dependence was first exploited by the development of the drug imatinib (Gleevec ® ) which inhibits both the Abl and Bcr-tyrosine kinases and has been successful in treating CML. In fact, the extraordinary interest in and development of protein kinase inhibitors was stimulated by the 2001 regulatory approval of imatinib for the treatment of Philadelphia chromosome-positive CML. Besides imatinib, nilotinib is another protein tyrosine kinase inhibitor targeting Bcr-Abl. In CML cases resistant to imatinib, broader spectrum tyrosine kinases such as dasatinib (Sprycel ® ), which blocks both Bcr-Abl, Src, and other tyrosine kinases, may be used (Table 14 .1). Inhibitors of receptor tyrosine kinases targeting epidermal growth factor receptor (EGFR; ErbB1; HER1; a member of the ErbB family of receptors), vascular endothelial growth factor receptors (VEGFRs), and platelet-derived growth factor receptors (PDGFRs) have also found use in the clinic as effective targeted antitumor drugs. Elevated EGFR tyrosine kinase activity is found in most solid tumors. The following is a list of the percentage expression of EGFR by some of the most common human cancers: nonsmall cell lung cancer 40-80, head and neck 80-100, gastric 33-81, colorectal 25-100, pancreatic 30-50, ovarian 35-70, breast 15-37, prostate 40-90 , and glioma 40-92%. Some receptor tyrosine kinase inhibitors include gefitinib and erlotinib (both inhibitors of EGFR), lapatinib (inhibits ErbB1 and ErbB2), vatalanib (inhibits VEGFR-1 and VEGFR-2), sorafenib (inhibits VEGFR, PDGFR, and c-Kit [CD117]), and sunitinib with a broad spectrum activity targeting VEGFR, PDGFR, FGFR, FLT3, and c-Kit. Other targeting strategies summarized in Table 14 .1 that interfere with signal transduction include the mTOR serine/threonine kinase inhibitors that target the Raptor complex; lipid kinase inhibitors (e.g., idelalisib, a phosphoinositide 3-kinase delta isoform [PI3Kδ] inhibitor); histone deacetylase inhibitors (drug examples include romidepsin and vorinostat) that arrest the cell cycle; the PML-RAR α oncoprotein (arsenic trioxide); and drugs (e.g., bexarotene) binding to retinoid receptors. Still other targeting strategies are represented by pralatrexate, a folate analog that accumulates in cancer cells overexpressing protein RFC-1, and proteasome inhibitors such as bortezomib and carfilzomib are active against the cells of multiple myeloma and mantle cell lymphomas in perhaps the most fascinating of all the current targeted mechanisms (Table 14 .1). These drugs inhibit proteasomes by binding to proteolytic catalytic sites in the 20S proteasome core (see below). This is thought to prevent degradation of pro-apoptotic factors permitting killing of cancer cells.

Imatinib mesylate (4-[(4-methyl-1-piperazinyl) methyl]-N- [4-methyl-3-[[4-(3-15pyridinyl )-2pyrimidinyl]amino]-phenyl]benzamide methanesulfonate) (Fig. 14. 2) is a protein tyrosine Some drugs exert their action(s) by more than one mechanism and might therefore be classified into more than one category. The classification shown is deemed to be the most appropriate one b Reactions known, or suspected, of having an immunological basis For severe skin reactions, the following management schedule has proved effective for achieving tolerance of therapeutic dosages of imatinib even after severe cutaneous reactions to the drug: prednisolone 1 mg/kg per day, tapered to 20 mg per day over several weeks along with the gradual reintroduction of imatinib (100 mg per day increased by 100 mg per week) given as the prednisolone dose is tapered off. This, of course, is only continued if the skin manifestations do not recur.

Oral desensitization to imatinib in patients with recurrent rash induced by the drug has been reported. Ten patients were subjected to a 4 h dosage procedure beginning with a dose of 10 ng followed by increases every 15 min. Four patients experienced no recurrence of rash after desensitization, four had recurrent rash that resolved after corticosteroid/antihistamine administration, and two patients each developed a rash and were unable to resume imatinib therapy.

Gefitinib and erlotinib are derivatives of 4-aminoquinazoline ( Fig. 14. 2). Both drugs are EGFR inhibitors, inhibiting the receptor's tyro-sine kinase domain by binding to the ATP-binding site of the enzyme. Approved by the FDA in 2003, gefitinib is indicated for locally advanced or metastatic nonsmall cell lung cancer with activated mutations of EGFR tyrosine kinase. EGFR is overexpressed by the cells of some cancers such as lung and breast leading to uncontrolled cell proliferation, the blocking of apoptosis, and increased production of angiogenic factors and metastasis. The mutations also incur increased sensitivity to tyrosine kinase inhibitors like gefitinib, but no clinically beneficial activity of the drug is shown in patients with EGFR-negative tumors. The most frequent adverse reactions to gefitinib, that is, reactions occurring in more than 20% of patients, are diarrhea and skin reactions. Reactions may be categorized by the affected organ: skin reactions like hand-foot skin reaction, pruritus, erythema, and papulopustular rash (Fig. 14.4 ) are common as are nail disorders, while bullous eruptions (erythema multiforme, SJS, and TEN) are rare. Note that hand-foot skin reaction ( Fig. 14 .5) should not be confused with hand-foot syndrome or acral erythema (Chap. 15, Sects. 15.2 and 15.2.5.1) seen during the administration of some cytotoxic anticancer drugs such as 5-fluorouracil and doxorubicin. Hand-foot skin reaction is distinguished by localized blisters or hyperkeratosis, whereas hand-foot syndrome shows diffuse, symmetrical erythematous, and edematous lesions on the palms and soles. Ocular (conjunctivitis, blepharitis) and gastrointestinal disorders, vascular effects (hemorrhage), and renal and urinary disorders are also common side effects of gefitinib. Interstitial lung disease has been found in 1.3% of patients, often of severe grade and occasionally fatal. Erlotinib is an EGFR type I receptor (HER1/ EFGR) tyrosine kinase inhibitor. These receptors are involved in the control of cell divisions and proliferation and by inhibiting their functions. Erlotinib limits tumor cell division and metastasis and may even help in initiating apoptotic cell death. A randomized, placebo-controlled, double-blind trial carried out by a National Cancer Institute of Canada Clinical Trials Group revealed that the main adverse responses to erlotinib were rash, fatigue, anorexia, diarrhea, nausea, ocular effects, infec-tion, vomiting, and stomatitis. Rash and diarrhea were the main reasons for dose reduction and interruption of treatment. In a 2009 warning, the FDA referred to rare serious gastrointestinal, skin, and ocular disorders in some patients taking erlotinib. As with other tyrosine kinase inhibitors, papulopustular rash, hand-foot skin reaction, and pigmentary changes are commonly seen. Serious eye conditions include corneal lesions, some patients develop gastrointestinal perforations, and rare bullous and exfoliative skin reactions, some leading to death, have occurred.

Second-generation Bcr-Abl inhibitors such as dasatinib and nilotinib may cause a pruritic skin rash with incidences of 23% and 34%, respectively. The pathogenesis is not well understood although it has been suggested that some kinases, with a role in epidermal homeostasis (e.g., PDGFR, RAS/RAF, Src family) and drug- Hand-foot skin reaction in a patient given sorafenib, a targeted inhibitor of some tyrosine kinases (including VEGFR and PDGFR) and Raf kinases. Note that hand-foot skin reaction is a distinct entity from handfoot syndrome or acral erythema which manifests as erythema, swelling, and desquamation of the palms and soles in cancer patients during non-targeted chemotherapy (see Chap. 15 induced decrease in TGF-β-stimulated collagen production, are involved. The third-generation Bcr-Abl inhibitor ponatinib is associated with hyperkeratotic rashes in about 40% of treated patients. BRAF inhibitors, vemurafenib and dabrafenib, cause keratosis pilaris-like rashes in 10-55% of treated patients and a Grover's disease-type rash in up to 27% of patients. Grover's disease is seen as an erythematous, polymorphic, pruritic, crusted papulovesicular eruption occurring mostly on the trunk. Such reactions occur more rarely with sorafenib and regorafenib. Interestingly, there are some rare reports of Grover's disease associated with mAb immune checkpoint inhibitor therapy including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (ipilimumab) and anti-programmed cell death-ligand 1 (PD-L1 (pembrolizumab) blockade (Sect. 14.2.1). The lipid tyrosine kinase PI3K P110δ inhibitor idelalisib occasionally induces a pityriasis rubra pilaris-like rash. Multikinase inhibitors like sorafenib and sunitinib frequently exhibit skin toxicity and produce fever, edema, and occasionally inflammatory actinic keratosis and bullous manifestations (Table 14 .1).

The inclusion of reactions to 17 kinase inhibiting drugs demonstrates the current importance of tyrosine and serine/threonine kinase inhibitors for the targeted treatment of an expanding range of tumors (Table 14 .1). While the aim of signal transduction therapy is to kill the cancer cells with minimal collateral damage, even a quick glance at the catalog of side effects in the table shows that, just as with the non-targeted drugs (but less so), cutaneous, gastrointestinal, and hematopoietic cells are often still affected. Cytotoxic effects such as anemia, thrombocytopenia, and neutropenia occur less often and usually with less severity than with, say, antimetabolites and alkylating agents, but a number of the targeted agents show their own fairly unusual effects including a lengthened QT interval, hand-foot skin reaction, and papulopustular rash. Inhibition of the EGFR in skin often produces xerosis, skin fissures, nail alterations, paronychia ( Fig. 14.6 ), periungual ulcers, and pruritus.

The ubiquitin-proteasome system has a central role in the turnover of proteins -in the regulation of cellular proteins involved in growth and survival and in the destruction of defective proteins. The proteasome consists of a hollow cylindrical or barrel-like 20S (0.7 MDa) proteolytic core capped at one or both ends by a 19S (0.9 MDa) regulatory particle or activator. These structures make up the single-capped proteasome complex or 30S double-capped form (Fig.14.7) . Note that the enzymically active double-capped proteasome complex, which is thought to be the functional unit in the cell, is usually referred to as the 26S (2.5 MDa) proteasome even though physicochemical analysis has revealed that the correct sedimentation coefficient is ~30S. The ~26S form probably represents the single-capped proteolytic core. Proteins that are defective in some way, for example, due to aging, incorrect folding, etc., are tagged by ubiquitin and directed to the proteasome for degradation via the endoplasmic reticulum degradation pathway. Cell-cycle pro-gression is dependent on the ubiquitin-proteasome pathway with its three proteolytic activities in the proteasome that are mediated by three β-subunits in the core: β2 trypsin-like, β5 chymotrypsin- 

Fig. 14.7 Diagrammatic representation of the proteasome and its role in protein degradation via the ubiquitinproteasome pathway. After being tagged with ubiquitin and unfolded for degradation on the 19S regulatory particles which aid the opening of a proteolytic gate in the 20S core, proteins are degraded into small peptides in the barrel-shaped core where β1 caspase-, β2 trypsin-, and β5 chymotrypsin-like activities reside. Regulatory particles are composed of a base (dark blue), lid (yellow-brown), and so-called arm (pink). The 20S proteolytic core may be capped at one or both ends by a 19S regulatory particle.

Proteasomes are thus referred to as single-capped (sedimentation coefficient ~26S) or double-capped (~30S). In the literature, the term 26S proteasome is often used incorrectly when referring to the double-capped form.

The double-capped complex is thought to be the functional proteasome unit in the cell like, and β1 caspase-like activities. Proteolytic activity of each of these subunits is associated with the N-terminal threonine residues in peptide bond hydrolysis. Cancer cells show higher proteasome activity than normal cells. Inhibition of proteasome function leads to intracellular accumulation of unwanted proteins and ultimately cell death, and, here too, cancer cells are more sensitive to the apoptosis-promoting effects of inhibition than normal cells. Proteasome inhibitors can induce apoptosis in leukemia-and lymphoma-derived cells without causing the death of non-transformed cells. Multiple myeloma cells synthesize and secrete large amounts of immunoglobulin, and this high rate of biosynthesis is thought to increase the sensitivity of the synthesized proteins to proteasome inhibitors by, for example, inducing the immunoglobulins into the unfolded state.

Most proteasome inhibitors are short peptides that serve as protein substrates in the proteasome 20S core where they target the active site threo-nine residues. Bortezomib, an N-protected dipeptide that contains a boron atom ( Fig. 14.8) , was the first proteasome inhibitor to be introduced into the clinic and is approved for treating relapsed multiple myeloma and mantle cell lymphoma. The drug inhibits proteasomes by binding with high affinity via the boron atom to the β-subunit chymotrypsin-and caspase-like proteolytic catalytic sites. It has little effect on the trypsin-like activity. Apoptosis is normally suppressed in mantle cell lines and myeloma cells, but proteasome inhibition may overcome this suppression and activate cell death. Bortezomib suppresses tumor growth and spread and angiogenesis through multiple mechanisms, and, in addition to directly inducing apoptosis of tumor cells, it mediates a myriad of biological effects including reduced adherence of myeloma cells to bone marrow cells, prevention of IL-6 production and signaling in myeloma cells, interference with the production of pro-angiogenic factors, and suppression of nuclear-factor-κ-light chainenhancer (NF-κB Fig. 14.8 Proteasome inhibitors used (or intended) for the treatment of relapsed multiple myeloma, mantle cell lymphoma, and some other tumors. Structures of the peptide boronates bortezomib and the orally active ixazomib (MLN9708, Ninlaro ® ) (used as the citrate) shows greater tissue penetration, and has a shorter half-life than bortezomib. The tetrapeptide epoxyketone carfilzomib leads to cell cycle arrest and induces apoptosis. The ocean bacteriumderived γ-lactam-β-lactone bicyclic salinosporamide A, also known as marizomib, inhibits normal proteasome action by binding to the β-subunit proteolytic sites in the 20S core. Still in early phase studies, oprozomib, structurally similar to carfilzomib, is highly selective to the β5 subunit of the 20S proteasome a stimulant in attempts to understand the molecular mechanisms underlying its clinical effectiveness and identifying new drugs acting on the same pathway. Gastrointestinal symptoms, thrombocytopenia, neutropenia, peripheral neuropathy, neuropathic pain, and fatigue are the most common side effects of bortezomib, and adverse cutaneous reactions to the drug are numerous (Table 14 .1). Rash (often pruritic) is frequently reported in more than 10% of patients (an incidence of 8-18% has been stated), and pruritus, erythema, urticaria, periorbital edema, and eczema are commonly seen. Bortezomib has been associated with cases of drug-induced Sweet's syndrome-like reactions (Fig. 14.9) or acute febrile neutrophilic dermatosis, a rare variant of this uncommon skin disease characterized by fever, an elevated neutrophil count, and erythematous lesions infiltrated by neutrophils. Besides Sweet's syndrome, reported cutaneous adverse drug reactions to bortezomib include ulceration, leukocytoclastic vasculitis, morbilliform exanthema, folliculitis-like rash, erythematous nodules and plaques, and perivascular dermatitis. Histological examination of a bortezomib-induced skin eruption showed a clinical picture similar to Sweet's syndrome but which differed by the presence of a significant number of CD30+ lymphocytes. The presence of these cells, which are seen during some treatments of blood malignancies, is not understood. Ocular symptoms are said to be common but rarely reported with bortezomib therapy. Cases with meibomitis, multiple chalazions, and blepharitis after treatment have been described. A separate 2016 report described 24 cases of bortezomib-related chalazia, usually multiple and involving the upper eyelid. The mean duration of therapy before the onset of chalazia was a little more than 3 months.

Subcutaneous infusion of bortezomib at 1 mg/ ml as an alternative to intravenous administration (2.5 mg/ml) was recently approved by the US Food and Drug Administration (FDA). This has proved a more convenient and less toxic route of administration and seems likely to become the standard form of the drug's delivery.

Carfilzomib, a tetrapeptide epoxyketone ( Fig. 14.8 ), is structurally and mechanistically different to bortezomib. It irreversibly binds to and inhibits chymotryptase activity but has less activity toward the other two enzymatic actions. The drug was approved by the FDA in 2012 for patients with relapsed and refractory multiple myeloma. It leads to cell cycle arrest and induces apoptosis in multiple myeloma, other hemato- logic malignancies, and some solid tumors. A potentially very important property is the drug's activity against primary multiple myeloma cells and cell lines resistant to bortezomib. Adverse reactions noted so far include pulmonary hypertension, dyspnea, cardiac toxicities, cytopenias, infusion reactions (Sect. 14.2.2.6), venous thrombosis, hemorrhage, tumor lysis syndrome (Sect. 14.2.2.7), hepatotoxicity, posterior reversible encephalopathy syndrome, acute renal failure, rash, and urticaria (Table 14 .1). In one study, peripheral neuropathy was observed in 12.4% of patients. Several studies have shown a 5-12% incidence of cardiac events in patients given carfilzomib. Like bortezomib, ixazomib (MLN9708, Ninlaro ® ) (used as the citrate) is also a peptide boronate (Fig. 14.8), but it is orally active, shows greater tissue penetration, and has a shorter halflife (18 versus 110 min). The drug is primarily an inhibitor of the chymotrypsin-like activity (β5) of the 20S proteasome core, and, like bortezomib, it inhibits NF-κB activation and has antitumor activity in multiple myeloma and some other hematologic malignancies. Besides common adverse reactions of diarrhea, nausea, and peripheral edema, FDA warnings and precautions for the drug relate to thrombocytopenia, gastrointestinal toxicities, peripheral neuropathy, hepatotoxicity, and cutaneous reactions, the most common of which are macular and maculopapular rash.

Still in clinical development, the orally active proteasome non-peptide inhibitor salinosporamide A, derived from natural sources, is a γ-lactam-βlactone bicyclic compound ( Fig. 14.8 ). Also known as marizomib, the drug is obtained from Salinispora tropica, a bacterium found in ocean sediments. Marizomib is an irreversible proteasome inhibitor that shows little effect on the caspase-like activity but inhibits chymotrypsin-and trypsin-like protease activities. Preclinical studies have demonstrated antitumor activity in models for multiple myeloma, hematologic malignancies, and solid tumors, and, importantly, marizomib does not show cross-resistance with other proteasome inhibitors. Phase I studies demonstrated relatively low toxic effects and no evidence of neuropathy or thrombocytopenia.

With structural similarities to carfilzomib, and similar to that compound and bortezomib, orally active oprozomib (Fig. 14.8) is highly selective to the β5 subunit of the 20S proteasome. Two early phase studies indicated what was said to be a tolerable safety profile with a low incidence of neuropathy, but diarrhea, nausea, and vomiting were a concern.

Besides peptide boronates like bortezomib, other synthetic compounds tested as proteasome inhibitors include peptide aldehydes, peptide epoxyketones, and peptide vinyl sulfones.

Serine/threonine mTOR kinase belongs to the phosphoinositide 3-kinase (PIK3)-related family. Used in oncology and as an immunosuppressive agent in organ transplants, mTOR inhibitor drugs are associated with a considerable number of adverse events (Table 14 .1). Prominent among these effects are interstitial lung disease, more common in oncology than transplantation, with up to 14% of renal cell carcinoma patients given everolimus developing pneumonitis. mTORassociated stomatitis, thought to be the result of toxic effects on the oral and nasal mucous membranes and manifesting as oral ulceration and distinct from mucositis seen during chemotherapy, is a common dose-limiting effect. Other potentially serious adverse responses to the drugs include hyperglycemia and new-onset diabetes mellitus, hyperlipidemia with increased levels of cholesterol and triglycerides common in up to 75% of patients, and reproduction effects producing decreased fertility, low sperm counts, sex hormone dysfunction, and high rates of ovarian cysts.

Human histone deacetylases (HDACs) are grouped into three classes, class I, class II, and class IV, with each class differing in location, enzyme activity, and substrate specificity. HDAC class I includes isoenzymes HDACs 1, 2, 3, and 8; HDAC class II includes HDCAs 4, 5, 6, 7, 9, and 10. HDACs 1, 2, 3, and 6 are highly expressed in different combinations of a number of cancers including breast, prostate, lung, colon, gastric, cervical, and esophageal cancers. Inhibition of classes I and II produces apoptosis of a wide range of tumor cells. HDAC inhibitors (HDACIs) lead to differentiation, cell-cycle arrest, and inhibition of migration, invasion, and angiogenesis in many different cancer cells. Some HDACIs are effective against different tumors either alone or in combination with other drugs or radiotherapy. In addition to romidepsin (approved for the treatment of cutaneous and peripheral T cell lymphomas), and vorinostat (approved for cutaneous T cell lymphoma) (Table 14 .1), two other drugs that inhibit the HDACI isoenzyme, belinostat (Beleodaq ® ) and panobinostat (Farydak ® ), are approved for cancer therapy by the FDA. Belinostat was approved by the FDA in 2014 for the treatment of peripheral T cell lymphoma, while in 2015 panobinostat was approved for multiple myeloma in combination with bortezomib and dexamethasone.

Myelosuppression involving thrombocytopenia, leukopenia, and anemia induced by all four of the above HDACIs is a frequent and often severe adverse event sometimes leading to serious hemorrhage and infection. Cardiac effects may occur, especially with QTc prolongation induced by vorinostat; hepatic effects may be seen, usually as raised serum transaminases and/ or bilirubin; and gastrointestinal effects of nausea, vomiting, and diarrhea may be severe, especially with panobinostat which now has an FDA Boxed Warning for diarrhea. Specific adverse effects listed for the four HDCAIs are romidepsin, infections and tumor lysis syndrome; vorinostat, pulmonary embolism, deep vein thrombosis, and hyperglycemia; belinostat, infections and tumor lysis syndrome; panobinostat, hemorrhage and cardiac ischemia. Post-marketing data from the EMA's EudraVigilance database of 455 reports of adverse events to panobinostat (the only HDACI approved by the EMA) revealed diarrhea as the most reported event (93 cases), followed by myelosuppression (81 cases, made up of thrombocytopenia 60, anemia 12, and neutropenia 9 cases), and cardiac/ECG effects (30 cases).

Acute promyelocytic leukemia (PML), which accounts for 10-15% of acute myeloid leukemia, is characterized by the translocation t(15;17). Expression of the PML/RARA oncoprotein is diagnostic of the disease and downregulated in response to all-trans retinoic acid (tRA; ATRA; tretinoin). Arsenic trioxide induces apoptosis and partial differentiation at high and low concentrations, respectively. Approved for PML cases resistant to tRA, arsenic trioxide targets the PML moiety of PML/RARA protein, inducing a complete remission rate in 85-90% of patients with newly diagnosed or relapsed PML. tRA induces terminal differentiation of acute promyelocytic leukemia cells by binding PML/RARA protein via the ligand-binding domain of RARA, but the majority of patients do not achieve complete remission and relapse within a few months. Clinical trials have shown that most acute PML patients can be cured by combination therapy of tRA and arsenic trioxide. Retinoic acid syndrome is a potentially fatal side effect of acute PML treatment (Table 14 .1). The syndrome occurs in about one quarter of acute promyelocytic leukemia patients treated with tRA and/or arsenic trioxide. Symptoms include fever, hypotension, weight gain, dyspnea with pulmonary infiltrates, pleuropericardial effusion, and renal failure. The realization that retinoic acid syndrome occurred in acute PML patients previously treated with arsenic trioxide but not in patients treated with tRA for other disorders led to the syndrome being termed differentiation syndrome. Some investigators have pointed out that the syndrome's symptom complex most closely resembles capillary leak syndrome (Sect. 14.2.2.8) and systemic inflammatory response syndrome (Sect. 14.2.2.9). The most frequently reported adverse effects elicited by tRA are similar to those seen in patients taking high doses of vitamin A, namely, fever, skin, and mucous membrane dryness, nausea and vomiting, bone pain, ocular disorders, rash, pruritus, and mucositis (Table 14 .1). Apart from differentiation syndrome, the most important and potentially serious adverse events following arsenic trioxide dosage are a number of cardiac conduction abnormalities including QTc interval prolongation and atrioventricular block.

Retinoids, structurally related to vitamin A, are a family of signaling molecules that regulate gene expression and influence, among other functions, vision, neural function, immunity, and cell proliferation and differentiation. Retinoic acid has an important role in cell development and differentiation and has found possible applications in cancer treatment suppressing breast, prostate, lung, ovarian, bladder, and skin cancers. Retinoic acid inhibits markers of cell proliferation including growth factors such as vascular endothelial growth factor (VEGF). In inhibiting tumor growth, angiogenesis, and metastasis, retinoic acid activates the retinoic acid receptor (RAR) or retinoic X receptor (RXR). As a result of the known anticancer activities of natural retinoids, synthetic retinoid receptor binders have been produced and investigated. The RXR synthetic agonist bexarotene, an oral retinoid therapy, is approved for the treatment of cutaneous T cell lymphoma (CTLC). Potential serious side effects of the drug (Table 14 .1) in the treatment of CTLC include rapid elevation of lipids and hypothyroidism. Hypertriglyceridemia of all grades occurred in 79% of patients who received the drug in early stage CTCL; hypercholesterolemia was reported in 48% of patients and hypothyroidism in 40%. Hyperlipidemia is a concern because of the associated increased risk of cardiovascular events.

Like other systemic targeted therapies, hormone therapy for some cancers such as breast and prostate can be as potent and effective as many other cancer treatments. Blockage, inhibition, or inactivation of hormones gives rise to side effects relevant to the targeted hormone. For women, many of these effects are similar to those experienced during menopause when estrogen levels decline, for example, hot flashes, weight gain, vaginal dryness, night sweats, and headaches. Symptoms induced by the administered hormone or analog may cause nausea, muscle and joint pain, hair loss, blood clots, and an increased risk of some cancers, for example, endometrial cancer and cancer of the uterus. Side effects in males include tiredness, hot flashes, nausea, loss of sex drive, impotence, and breast tenderness. Due to a decrease in the body's natural hormone levels, an increased risk of osteopo-rosis is possible for both sexes. A more complete list of hormone-related adverse effects including possible cutaneous reactions, some severe, is set out in Table 14 .1.

From their earliest examples, specifically targeted mAbs directed to selected antigens of many different tumors appeared to offer great promise for both patients and clinicians. Now, with 88 mAbs (April 2020) currently approved by the FDA and/or EMA, 36 or 41% are indicated for the treatment of human cancers covering hematologic, solid tumor, and cutaneous malignancies.

The 36 mAbs currently approved by the FDA for cancer therapy are listed in Table 14 .2 together with trade names, antibody subclass, extent of species recognition, antibody target, mechanism of action, and approved indications.

In achieving the wide and diverse coverage of a large variety of tumors, a range of different targets and mechanisms of action have been sought. Molecular mechanisms employing mAb-targeted therapies are predominately direct cytotoxic action against cancer cells, an effect on signaling pathways, or immune modulatory effects leading to the indirect destruction of cancer cells. For a still small but increasing number of approved mAbs, a direct cytotoxic action is achieved by using an antibodydrug conjugate (ADC) (Chap. 13, Sect. 13.1.5), whereby cell killing is effected by an attached bioactive payload of a potentially lethal toxin, drug, cytokine, or radionuclide. Figure 14 .10 shows three examples of ADCs, gemtuzumab ozogamicin, ado-trastuzumab emtansine, and brentuximab vedotin, each summarized in Sect. 14.2.1. Examples of cell-destructive immune modulatory effects include antibody-dependent cell cytotoxicity (ADCC) and modulation of immune checkpoints by the targeting of inhibitory pathways regulating signaling between T cells and antigenpresenting cells. Specifically, 23 different targets have been utilized so far (including, at April 2020, Trop-2, targeted by sacituzumab govitecan-hziy [Table 14 .2]) in obtaining the present battery of Gastric or GE junction adenocarcinoma: As single agent or in combination with paclitaxel after prior fluoropyrimidine or platinum chemotherapy. Colorectal cancer: For patients with disease progression on or after bevacizumab, oxaliplatin, and fluoropyrimidine therapy. Also approved by the EMA as monotherapy and for use with paclitaxel for advanced gastric cancer or GE junction cancer Table 14 .2 (continued) approved antibody preparations as efforts continue to further understand mechanisms underlying tumor growth, avoidance of immune recognition, and metastasis while extending the coverage of different neoplasms with new mAbs and improving on the effectiveness of existing agents.

Following are summaries of individual targets of the 36 approved anticancer mAbs together with the rationale for their use (Table 14 .2). The trifunctional hybrid mAb catumaxomab is a dual specificity mouse-rat hybrid mAb (Removab ® ) composed of a mouse kappa light chain and IgG2a heavy chain and a rat lambda light chain and IgG2b heavy chain. Binding of the Fc region with Fcγ receptors provides a third functional binding site. The mouse Fab binds to EpCAM, the rat Fab binds to CD3, and the hybrid Fc fragment binds to FcγRI (CD64), FcγRIIa (CD32), and FcγRIIIa (CD16a) on macrophages, NK cells, dendritic cells and mononuclear cells. EpCAM (CD326) is a transmembrane glycoprotein, expressed on the surface of tumor cells. It promotes tumor growth and metastasis and is overexpressed on epithelial tumors of the gastrointestinal tract, esophagus, head, neck, lung, liver, kidney, ovary, pancreas, prostate, and a number of other organs and tissues. Overexpressed in advanced cases of cancer, EpCAM is also expressed on tumor cells in malignant effusions, hence its indication for malignant ascites. T cellinduced killing, ADCC, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP) results from the trifunctional action of catumaxomab.

Blinatumomab (Blincyto ® ) (Table 14. 2), used to treat acute lymphoblastic leukemia, is not a standard 2H and 2 L chain mAb but a so-called bispecific T-cell-engaging (BiTE) fusion protein. This antibody construct, a ~55 kDa protein derived from the linkage of four peptide chains from four different genes, is composed of two (Table 14 .2) target the human B lymphocyte-restricted differentiation antigen Bp35, or CD20, a 33-35 kDa transmembrane glycosylated phosphoprotein expressed on the surface of B cells (but not plasmablasts and mature plasma cells) at all stages of their development and also on B cell lymphomas, B cell chronic lymphocytic leukemia, hairy cell leukemia, and melanoma cancer stem cells. CD20 may be involved in transmembrane signaling controlling growth and cell death in some tumors, it is not normally shed from cells, it is internalized after binding to antibody, and due to its B cell expression in non-Hodgkin lymphoma and chronic lymphocytic leukemia, it has been exploited as a target for mAbs for the treatment of lymphomas.

Brentuximab vedotin (Adcetris ® ) (Table 14. 2) is a chimeric mAb conjugated to the cytotoxic agent monomethyl auristatin E to form an ADC targeted to CD30 (TNFRSF8) (Fig. 14.10) , a 120 kDa cell membrane glycoprotein of the tumor necrosis receptor family expressed on activated T and B lymphocytes. CD30, overexpressed in Hodgkin lymphoma, anaplastic large-cell lymphoma, cutaneous T cell lymphoma, and mediastinal B cell lymphoma, protects against autoimmunity by limiting CD8 T cells and by interaction with TRAF2 and TRAF5 (TNF receptor-associated factors 2 and 5), regulating apoptosis via (NF-κB) activation. Once linked to its target, the mAb's attached toxin is internalized, disrupting microtubules in the lysosomes and inducing apoptosis.

Alemtuzumab (Campath ® ; MabCampath ® ), a humanized mAb with complementaritydetermining regions from a rat mAb, is targeted to CD52 (Campath-1 antigen) (Table 14. 2), a 21-28 kDa 12 amino acid glycoprotein of unknown function with a single N-linked oligosaccharide. CD52 is expressed on mature normal and malignant B and T lymphocytes, monocytes, macrophages, NK cells, a subpopulation of granulocytes, and dendritic cells as well as lymphoid and male sexual organs. Widely used for the treatment of B cell chronic lymphocytic leukemia resistant to alkylating agents until 2012, alemtuzumab exerts its antitumor action primarily by ADCC and with a contribution from CDC and induction of apoptosis. After being withdrawn and relaunched as Lemtrada ® for multiple sclerosis, a small number of patients receive it through a specific access program, and some off-label cancer therapy usage remains.

Cetuximab (Erbitux ® ), panitumumab (Vectibix ® ), and necitumumab (Portrazza ® ) target epidermal growth factor receptor (EGFR, HER1, ErbB1), a transmembrane glycoprotein cell surface receptor and member of the ErbB family of receptors (Table 14 .2). The ErbB family is a subfamily of closely related receptor tyrosine kinases, themselves important targets for cancer therapy because of their central role in growth factor signaling leading to cell proliferation, differentiation, and survival. In addition to the importance of EGFR in normal cellular functions and survival, EGFR may contribute to the development of cancerous cells through effects on angiogenesis, cell cycle progression, inhibition of apoptosis, and metastasis. EGFR and its ligands are associated with growth of cancer cells, and elevated EGFR tyrosine kinase activity is found in many solid tumors. Table 14 .3 shows the percentages of overexpression of EGFR in some common human solid tumors. After receptor activation by binding its specific ligands and dimerization, the receptor-ligand complex is internalized, autophosphorylation occurs, and the tyrosine kinase signal transduction pathways lead to regulation of gene transcription involved with cell growth and survival, motility, and proliferation. The EGFR-binding mAbs bind the receptor on both normal and tumor cells, competitively inhibiting binding of the normal ligands. Ligand-induced autophosphorylation of the receptor and activation of receptor-associated kinases are thus prevented, resulting in inhibition of cell growth and decreases in proinflammatory cytokines and the production of vascular growth factor.

Bevacizumab (Avastin ® ) (Table 14. 2) binds to, and inhibits, human vascular endothelial growth factor-A (VEGF-A), an important regulator of blood vessel formation in health and disease. Acting in endothelial cells through a family of related receptor tyrosine kinases. VEGF-A also has a major role in inducing angiogenesis and the pathogenesis of a wide range of human diseases including cancers. VEGF-A binds to receptors VEGFR-1 (also called Flt-1) and VEGFR-2 (KDR/Flk-1); VEGFR-1 recruits hematopoietic stem cells, while VEGFR-2 regulates vascular endothelial function. Increased expression of VEGF-A occurs in many human solid tumors, promoting angiogenesis and assisting aggressive tumor growth. By binding to VEGF-A, bevacizumab prevents both activation of VEGFR-2 and the generation of new tumor vasculature, depleting the blood supply necessary for tumors to grow and proliferate. (Table 14 .2) has binding specificity for VEGFR-2 (CD309; also known as kinase insert domain-containing receptor KDR), the receptor mediating angiogenesis. VEGF-A and VEGFR-2 are often upregulated in cancers, and since uncontrolled angiogenesis is a major contributor to tumor growth, targeted inhibition of the development of blood vessels is a logical antitumor strategy. Ramucirumab targets VEGFR-2 with high affinity and thereby inhibits receptor activation and signaling, intracellular Ca 2+ mobilization, proliferation and migration of endothelial cells, and tumor angiogenesis.

Pertuzumab (Perjeta ® ), trastuzumab (Herceptin ® ), and ado-trastuzumab emtansine (Kadcyla ® ) target Human epidermal growth factor receptor 2 or HER2 (also known as HER2/ neu, ErbB2, CD340 and p185), a member of the erythroblastic leukemia viral oncogene (gene ErbB) family (Table 14 .2). The structure of the HER2 receptor consists of an extracellular ligand-binding domain, a transmembrane spanning section, and an intracellular protein tyrosine kinase domain. An intracellular tyrosine kinase domain also exists for HER1 and HER4 but not HER3. HER2 is inactive in the monomeric state and needs to be in the dimeric or oligomeric state for activation. There is no known natural ligand for HER2. Activation of receptor kinase function proceeds mainly via ligand-mediated hetero-or homodimerization, but ligand-independent receptor activation can occur with activation being triggered by overexpression of HER2 and a high concentration of cell surface receptors that results in the formation of HER2/HER2 homodimers. Overexpression of HER2 leads to constitutive activation of the growth factor signaling pathways with a consequent favorable environment for breast cancer cell growth. For receptor dimerization, HER2 is the preferred and most important partner. HER3 has a high affinity for HER2, and the HER2/HER3 heterodimer appears to be the most potent in promoting the signal transduction process and tumor promotion. By blocking dimerization, pertuzumab and trastuzumab inhibit HER2 signaling and mediate ADCC. Like trastuzumab, the ADC ado trastuzumab emtansine inhibits HER2 signaling, medi- ates ADCC, and inhibits overexpression of HER2. In addition, the ADC undergoes receptormediated internalization, lysosomal degradation, binding of the released thiol-containing maytansinoid toxin (Fig. 14.10) to microtubules, cell cycle arrest, and apoptotic death of the cell. Denosumab (Xgeva ® ; Prolia ® ) (Table 14. 2) is specific for receptor activator of nuclear factor kappa B ligand, otherwise known as RANKL, a cytokine and member of the tumor necrosis factor (TNF) family (also called TNFSF11) responsible for bone resorption. RANKL stimulates osteoclast formation, activation, adherence, survival, and ultimately resorption of bone, and its inhibition results in an increase in bone density, volume, and strength. Marketed under two trade names, denosumab as Prolia ® has approved cancer use indications for the treatment of men at high risk of fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer and for the treatment of women at high risk of fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. As Xgeva ® , denosumab is approved for the prevention of skeletal-related events in patients with bone metastases from solid tumors and the treatment of giant cell tumor of the bone.

Ipilimumab (Yervoy ® ) (Table 14. 2) binds the extracellular domain of the protein receptor, human cytotoxic T lymphocyte antigen 4 or CTLA-4 (also known as CD152), a member of the immunoglobulin superfamily. CTLA-4, expressed on the lymphocyte surface, has a critical role as an inhibitory regulator during the early stages of T cell expansion. When it competitively interacts with the B7 ligands on antigen presenting cells (see Chap 3, Sect. 3.2.1), interference with IL-2 secretion and receptor expression and downregulation of the T cell response results. When bound to the B7 complex (where it binds with greater affinity than CD28), CTLA-4 can be viewed as an immune "off" switch modulating over-activity of T cells and maintaining tolerance to self-antigens ( Fig. 14.11) . However, suppressing the immune response can allow cancer cells to be recognized as self and multiply in the absence of antitumor immune challenge. Recognition of the crucial role of CTLA-4 as an inhibitory regulator of the T lymphocyte response led to the blockade of the receptor by the specific mAb ipilimumab. (Table 14. 2) is a chimeric human-mouse mAb targeted to the soluble bioactive forms of interleukin-6 (IL-6). IL-6, produced by many different cells including lymphocytes, monocytes, fibroblasts, and endothelial and cancer cells, is a pleiotropic cytokine with a complex action producing both proinflammatory and antiinflammatory effects. The balance between proand anti-inflammatory effects of IL-6 appears to be crucial in the pathogenesis and/or response to some diseases. In fact, increased levels of IL-6 are known to be associated with a variety of diseases including neoplasias. Cancers associated with increased production of IL-6 include renal cell carcinoma, prostate and bladder cancers, some neurologic cancers, and particularly multiple myeloma and the B cell lymphoproliferative disorder, Castleman's disease. Castleman's disease may be unicentric (localized) or multicentric. IL-6, produced in excess, has a central role in the latter form which is characterized by generalized lymphadenopathy with systemic symptoms and with its production of B lymphocytes, plasma cells, secretion of VEGF, and autoimmune reactions. IL-6 binds to its receptor IL-6R, but the resultant complex needs to associate with the protein gp130 (CD130), expressed on almost all cells, to initiate intracellular signaling. IL-6R is also found in soluble form (sIL-6R). The soluble receptor can bind IL-6, and, in a process called trans-signaling, cells expressing gp130, even in the absence of IL-6R, can respond to the complex of IL-6 -sIL-6R. Siltuximab blocks the binding of IL-6 to both the membrane-bound and soluble IL-6 receptors, thereby preventing the formation of the signaling complex with gp130 on the cell surface.

Monoclonal antibodies targeting programmed cell death protein 1 (PD-1): pembrolizumab (Keytruda ® ), nivolumab (Opdivo ® ), and cemiplimab-rwlc (Libtayo ® ) (Table 14 .2). The programmed death-1 receptor PD-1 (CD279), a transmembrane protein receptor expressed on T cells during thymic development and on CD4+ and CD8+ T cells, B lymphocytes, NK cells, B cells, monocytes, and some dendritic cells, acts as an important immune checkpoint, playing a critical role in cancer immunology. Although PD-1 has two ligands, PD-L1 (CD274; B7-H1) and PD-L2 (CD273; B7-DC), the affinity of PD-L2 for PD-1 is three times higher than the affinity of PD-L1. PD-L1 is expressed on fewer cells, and cell types than PD-L2 and PD-L1 appears to be associated with increased aggressiveness of cancers and death. Like CTLA-4, PD-1 negatively regulates T cell activation. Signaling induced by the binding of PD-1 with its ligands suppresses T cell proliferation and activity. Upregulation of PD-L1 ligands occurs in some tumors. The binding of cancer cells, which often express PD-L1, induces receptor inhibitory signaling preventing expansion of activated T cells and allowing the tumor cells to avoid immune recognition and attack. Reversing such checkpoint inhibition can be achieved by selectively blocking the signaling pathway, reversing the checkpoint inhibition, and restoring the T cell-mediated response to the tumor. The mAbs pembrolizumab, nivolumab, and cemiplimabrwlc bind to PD-1 and prevent interaction of the receptor with its ligands (Fig. 14.11 ).

PD-L1 may be expressed on tumor cells and can contribute to inhibition of the antitumor response. PD-L1 appears to be associated with increased aggressiveness of cancers and death. Monoclonal antibodies targeting programmed cell death-ligand 1 (PD-L1), atezolizumab (Tecentriq ® ), avelumab (Bavencio ® ), and durvalumab (Imfinzi ® ) bind to PD-L1 (Table 14. 2), blocking interaction with PD-1 and B7.1 and thus removing the PD-L1 -PD-1-mediated inhibition of the activated antitumor response.

Dinutuximab (Unituxin ® ) (Table 14. 2) binds the tumor-associated carbohydrate antigen, sialic glycosphingolipid (ganglioside), disialoganglioside GD2, a short sialated polysaccharide linked to ceramide through a β-glycosidic linkage and found highly expressed on neuroectoderm-derived cancers such as neuroblastoma, melanoma, brain tumors, osteosarcoma, and Ewing's sarcoma in children. Administered as passive antibody therapy, dinutuximab should be used in combination with GM-CSF, IL-2, and 13-cis-retinoic acid.

Daratumumab (Darzalex ® ) (Table 14. 2) is targeted to the 48 kDa glycoprotein CD38 (cyclic ADP ribose hydrolase), a surface antigen expressed by multiple myeloma cells and found on many immune cells including CD4+, CD8+, B lymphocytes, and natural killer (NK) cells. The mAb acts by inhibiting the growth of tumor cells expressing CD38, leading to apoptosis by Fc-mediated cross-linking and cell lysis induced via CDC, ADCC, and ADCP. In April 2020, the CD38-targeted chimeric IgG1κ cytolytic mAb, isatuximab-irfc (Sarclisa ® ), was approved by the FDA for the treatment of multiple myeloma (Tables 14.2 

Elotuzumab (Empliciti ® ) (Table 14. 2) targets the cell surface glycoprotein receptor CS1 (also known as CD2 subunit 1, SLAMF7, and CD319), a member of the signaling lymphocytic activation molecule (SLAM) receptor family. SLAMF7 is highly expressed on myeloma cells but not on other tissues, including hematopoietic stem cells. Elotuzumab should be given in combination with lenalidomide and dexamethasone. Elotuzumab targets SLAMF7 on myeloma cells and natural killer (NK) cells, facilitating the latter to kill myeloma cells through ADCC. The addition of lenalidomide to the mAb therapy results in enhanced NK cell-mediated killing.

The ADCs, inotuzumab ozogamicin (Besponsa ® ) and moxetumomab pasudotox-tdfk (Lumoxiti ® ) (Table 14. 2), inhibit B-cell receptor calcium signaling by targeting CD22, a sialic acid binding immunoglobulin-like lectin expressed on many B-cell malignancies. Inotuzumab ozogamicin is a conjugate of the mAb inotuzumab and a cytotoxic calicheamicin derivative. Following internalization and intracellular hydrolytic cleavage of the cytotoxic complex, the released toxin induces double-strand DNA breaks, cell cycle arrest, and apoptotic death. Moxetumomab pasudotox-tdfk is a recombinant immunotoxin fusion protein composed of the Fv fragment of an anti-CD22 monoclonal antibody fused to a 38 kDa fragment of Pseudomonas exotoxin A, PE38. Following binding to CD22 on the cell surface of B cells, internalization of the toxin complex results in ADP-ribosylation of elongation factor 2, inhibition of protein synthesis, and apoptotic cell death.

Gemtuzumab ozogamicin (Mylotarg™) ( Table  14. 2) is a CD33-directed ADC made up of the mAb gemtuzumab linked to a cytotoxic calicheamicin derivative (Fig. 14.10) . Following binding to CD33 on tumor cells, internalization of the cytotoxic complex, and intracellular hydrolytic cleavage, toxin-induced double-strand breaks of DNA leads to cell cycle arrest and apoptotic cell death. (Table  14. 2) is an ADC targeted to the B cell-specific surface protein CD79b with cytotoxic activity against dividing B cells. After binding to CD79b, the ADC is internalized, and the linked cytotoxic agent monomethyl auristatin E is cleaved by lysosomal proteases, freeing the toxin to bind to microtubules and kill dividing cells by inhibiting cell division and inducing apoptosis.

Olaratumab (Lartruvo ® ) (Table 14. 2) binds platelet-derived growth factor alpha receptor (PDGFR-α), a receptor tyrosine kinase expressed on cells of mesenchymal origin and some tumor and stromal cells, including sarcomas. Signaling through this receptor has a role in cell growth, chemotaxis, and differentiation and can influence cancer cell proliferation, metastasis, and the tumor microenvironment. Olaratumab interacts with PDGFR-α preventing binding to its ligands, ligandinduced receptor activation, and downstream signaling. By disrupting the PDGFR-α signaling pathway, olaratumab exerts antitumor activity against selected sarcoma cell lines.

In April 2020, sacituzumab govitecan-hziy (Trodelvy TM ), an ADC prepared by conjugating the toxic topoisomerase I inhibitor govitecan (SN-38) to a humanized IgG1κ mAb against trophoblastic cell surface antigen-2 (Trop-2), was approved in the USA for the treatment of metastatic triple negative breast cancer (Tables 14.2 

Monoclonal antibodies used for cancer immunotherapy are highly specific for their targets, less prone to drug-drug interactions, and generally better tolerated than small molecule chemotherapeutic drugs. Despite these attributes and their specifically targeted nature and consequent hoped-for safety benefits, their range of adverse effects remains wide with some events immunemediated and others non-immune or even the result of direct cytotoxic effects (Table 14 .4 and Box 14.1). Limitations on the use of mAbs include their size which may limit tissue penetration, their (Table 14. 2), the FDA has issued warnings and precautions for infusion reactions, neutropenia, second primary malignancies, and EFT. ADCC antibody-dependent cell-mediated cytotoxicity, AHUS atypical hemolytic syndrome, ALT alanine transaminase, AML acute myelogenous leukemia, AP alkaline phosphatase, AST aspartate transaminase, BMS bone marrow suppression, CHF congestive heart failure, CLS capillary leak syndrome, CNS central nervous system, CRS cytokine release syndrome, CTLA-4 cytotoxic T lymphocyte-associated antigen 4, EFT embryo-fetal toxicity, EGFR epidermal growth factor receptor (HER1, ErbB-1), EM erythema multiforme, EpCAM epithelial cell adhesion molecule, GD2 disialoganglioside expressed on tumors of neuroectodermal origin, GI gastrointestine/gastrointestinal symptoms, eg. nausea, diarrhea, vomiting, constipation, etc.; 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 Immune-mediated reactions due to T cell activation and proliferation -enterocolitis, hepatitis, dermatitis, neuropathies, endocrinopathies and other immune-mediated reactions including cutaneous and ocular manifestations aa Immune-mediated pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, and hyperthyroidism ab Immune-mediated colitis, hepatitis, nephritis, hypothyroidism and hyperthyroidism 14.2 Monoclonal Antibodies for Cancer Therapy instability, the expression of specifically targeted tumor antigens on normal cells, lack of oral absorption, immunogenicity, and the possibility of hypersensitivity reactions to the proteins. Even so, the relatively non-specific, nondisciminatory approach of killing rapidly dividing normal, healthy cells by promiscuous binding to off-target sites with consequent cytotoxicity and other wide-ranging side effects often makes treatment regimens with small molecule antineoplastic agents difficult to manage and a less attractive option than mAb-targeted therapies despite their limitations.

Cytopenias are a well-known side effect of mAb therapy (Box 14.1), but the underlying mechanisms frequently remain unexplored, and types II and III hypersensitivities induced by the antibodies may be underdiagnosed and under-reported. Thrombocytopenia, for example, a well-known adverse event following the use of many small molecule chemotherapeutic drugs, is much more rarely reported during and after mAb treatments. Boxed warnings have been issued for the risk of severe cytopenias with ibritumomab tiuxetan and alemtuzumab, and for severe neutropenia with sacituzumab govitecan-hziy, while general warnings and precautions are set down for obinutuzumab (thrombocytopenia, neutropenia); ofatumumab (cytopenias); brentuximab vedotin (neutropenia); trastuzumab (neutropenia); and ado-trastuzumab emtansine (thrombocytopenia). Listed among the other warnings/adverse events for the 36 anticancer mAbs are cytopenias for catumaxomab, brentuximab vedotin, and pertuzumab; lymphopenia for elotuzumab; lymphopenia and leukopenia for blinatumomab; neutropenia for rituximab; thrombocytopenia and neutropenia for daratumumab; thrombocytopenia and anemia for trastuzumab; thrombocytopenia, lymphopenia, anemia, and neutropenia for dinutuximab; thrombocytopenia, leukopenia, and neutropenia for inotuzumab ozogamicin; thrombocytopenia and neutropenia for polatuzumab vedotin-piiq; and thrombocytopenia, lymphopenia, and neutropenia for olaratumab (Table 14 .4).

Immunogenicity is always a safety concern for mAbs, even those that are fully human, since the possibility of generating anti-idiotype antibodies remains (Chap. 13, Sect. 13.1.1). Apart from such recognition of foreign antigens, patient responses to mAbs cover the full range of hypersensitivities Monoclonal antibodies are proteins, and anaphylaxis mediated by IgE antibodies is the classic example of a type I hypersensitivity. The possibility of an anaphylactic reaction to a mAb is therefore always considered especially for therapies known to be of greatest potential risk, namely, chimeric proteins used for cancer therapy containing mouse and/or rat sequences (catumaxomab, blinatumomab, ibritumomab tiuxetan, brentuximab vedotin, cetuximab, rituximab, siltuximab, and dinutuximab) (Table 14 .4 and Box 14.2). In fact, the observed incidences of such reactions are actually quite small. Anaphylaxis has been reported for, at least, cetuximab, rituximab, brentuximab, bevacizumab, trastuzumab, pertuzumab, ibritumomab, dinutuximab, and gemtuzumab ozogamicin, but reactions may be underestimated because of the inability to distinguish true type I IgE-mediated anaphylaxis from some severe infusion and anaphylactoid reactions and the frequent failure to test for the involvement of a type I hypersensitivity response by skin testing, tryptase assay, and the presence of mAb-specific IgE antibodies (Chap. 4).

Apart from abciximab (Chap. 13), targeted to platelet glycoprotein GP IIb/IIIa and used for the prevention of cardiac ischemic complications, there appears to be a dearth of convincing evidence for the involvement of mAbs in type II hypersensitivity reactions. Immune thrombocytopenia is a complex autoimmune disease, the pathogenesis of which remains unclear although both antibody-mediated and T cell-mediated platelet destruction are involved. Thrombocytopenia is a well-known adverse event following rituximab mono-or combination therapy with an incidence of ~1.7%, but a clear demonstration of an immune mechanism is lacking. In one study it was not possible to implicate rituximab-dependent antibodies, and IL-1 and IL-6 Box 14.2 Hypersensitivity Reactions to mAbs Used for Cancer Therapy • Type I: There is a low incidence of reactions. Chimeric molecules, catumaxomab, ibritumomab, cetuximab, rituximab, and brentuximab carry warnings. Anaphylaxis is reported for cetuximab, rituximab, brentuximab, ibritumomab, trastuzumab, pertuzumab, bevacizumab, dinutuximab, gemtuzumab, ozogamicin, sacituzumab govitecan-hziy. • Type II: There is little or no good evidence for immune thrombocytopenia to an anticancer mAb (c.f. abciximab). Rituximab-induced late-onset neutropenia may be immune-mediated. Autoimmune hemolytic anemia is induced by rituximab and alemtuzumab. • Type III: Cellular and humoral processes may be involved in some cases of mAbinduced vasculitis. Chimeric mAbs can induce serum sickness (e.g., rituximab). • Immune-mediated (hypersensitivity) pneumonitis involves both type III and type IV hypersensitivity reactions mediated by immune complexes and Th1 and likely Th17 T cells, respectively. Reactions caused by mAb PD-1 (nivolumab, pembrolizumab, cemiplimab-rwle) and PD-L1 (atezolizumab, avelumab, durvalumab) immune checkpoint inhibitors. • Precise mechanisms of immune-mediated colitis, hepatitis, nephritis, hypothyroidism, and endocrinopathies induced by mAb PD-1 and PD-L1 checkpoint inhibitors not yet established. • Type IV: Rare reactions to ibritumomab, brentuximab, pembrolizumab, and especially rituximab (SJS, TEN, lichenoid dermatitis, vesiculobullous dermatitis, and paraneoplastic pemphigus). Dermatitis induced by catumaxomab, bevacizumab, denosumab, ipilimumab, panitumumab. Immune-mediated dermatologic adverse reactions induced by durvalumab and cemiplimab-rwlc may be type IV reactions, but the mechanisms are not yet unequivocally established.

were not increased but complement levels were elevated leading investigators to conclude that mAb-induced transient thrombocytopenia might be mediated by complement activation and associated with cytokine release syndrome (CRS). Alemtuzumab and trastuzumab are other mAbs implicated in treatment-related severe thrombocytopenia. Three percent of patients given alemtuzumab developed potentially fatal thrombocytopenia, and 5 of 11 patients with peripheral T cell lymphoproliferative disorders developed lymphopenia, neutropenia, and thrombocytopenia. Rituximabinduced neutropenia is a suspected example of a mAb-induced type II hypersensitivity. It has been implicated in both early and late forms of the condition. Late-onset neutropenia manifests at least 4 weeks after the cessation of therapy; it occurs with a comparatively high incidence (4-23%) and appears to be caused by a different mechanism than early-onset neutropenia. Direct cytotoxicity does not seem to be involved, and autoantibodies may be responsible for the rituximab-induced disease. Rituximab has also been implicated as a cause of severe anemia (incidence 1.1-5.2%), severe autoimmune hemolytic anemia, intravascular hemolysis, rhabdomyolysis, renal failure, bone marrow necrosis, and multiple organ ischemia due to anti-Pr cold agglutinins. At least two mAbs, rituximab and alemtuzumab, have been implicated in the induction of pure red cell aplasia and autoimmune hemolytic anemia (Table 14 .4 and Box 14.2).

Hypersensitivity vasculitis and serum sicknesslike reactions are examples of type III hypersensi-tivity responses known to be provoked by mAbs although the latter condition is probably underdiagnosed and underreported. Again, the humanmouse antibody rituximab has most often been the culprit mAb involved, an example of the greater potential of chimeric antibodies to induce the reactions. It has been claimed that rituximab-induced serum sickness-like reactions can occur in up to 20% of treated patients, especially in those with hypergammaglobulinemia and autoimmune diseases, particularly autoimmune thrombocytopenia. Figure 14 .12 shows an example of mAb-induced cutaneous vasculitis during treatment with the fully human TNF-targeted adalimumab.

Checkpoint inhibitors ipilimumab that targets CTLA-4, nivolumab, pembrolizumab, and cemiplimab-rwlc that block PD-1, and atezolizumab, avelumab, and durvalumab that block PD-L1, provoke a number of immune-mediated reactions. Perhaps one of the most dangerous and reported reaction is immune-mediated, or hypersensitivity, pneumonitis, a combined type III and IV hypersensitivity reaction in a Th1/Th17 response. Compared to nivolumab, pembrolizumab showed an increase in grade 3-5 pneumonitis, a difference attributed to the small specificity differences in the PD-1 mAb combining sites. Compared with nivolumab or ipilimumab monotherapy, combined therapy with these two mAbs showed significant increases in grades 1-5 and 3-5 pneumonitis. As well as the immune-mediated lung reactions, anti-PD-1 and anti-PD-L1 therapy may induce immune-mediated colitis, hepatitis, endocrinopathies, nephritis, and thyroid reactions. Presumably, these immune reactions may also have at least a component of a type III hypersensitivity response (Table 14 .4 and Box 14.2).

Monoclonal antibody-induced type IV hypersensitivity reactions of the skin include allergic contact dermatitis, psoriasis, maculopapular exanthema, fixed drug eruption, acute generalized exanthematous pustulosis, erythema multiforme, DRESS, and cutaneous bullous toxidermias such as SJS and TEN (Table 14 .4 and Box 14.2). The last two of these reactions are rare with most reported cases restricted mainly to ibritumomab tiuxetan, brentuximab vedotin, and rituximab. Lichenoid dermatitis, vesiculobullous dermatitis, and paraneoplastic pemphigus have also occurred in response to rituximab, and a case of lichenoid eruption occurred after obinutuzumab. Other mAb-induced cutaneous manifestations with features seemingly common to a type IV response may be true type IV hypersensitivities, but mechanisms remain to be established, for example, cases of dermatitis induced by catumaxomab, bevacizumab, denosumab, ipilimumab, and panitumumab. In fact, panitumumab carries a black box warning for dermatologic toxicity. Cutaneous acneiform rash reactions that are not genuine hypersensitivities are seen with the EGFRtargeted mAbs cetuximab, panitumumab, and necitumumab (Sect. 14.2.2.5).

Classified under the heading drug-induced lung diseases (DILDs), these pulmonary adverse events make up a heterogeneous group of diseases, most still of unknown, or poorly understood, mechanism of action. Although there are a number of classifications, DILDs have been grouped here into four categories: interstitial pneumonitis and fibrosis; acute respiratory distress syndrome (ARDS); bronchiolitis obliterans organizing pneumonia (BOOP); and hypersensitivity pneumonitis. At least 14 of the currently approved mAbs for cancer therapy have been implicated in some form of pulmonary toxicity in immune-mediated pneumonitis, dyspnea • Fully human antibodies -Panitumumab: interstitial lung disease, lung infiltrates, pneumonitis, pulmonary fibrosis -Nivolumab: immune-mediated pneumonitis, dyspnea -Cemiplimab-rwlc:

immune-mediated pneumonitis -Avelumab:

immune-mediated pneumonitis -Durvalumab:

immune-mediated pneumonitis, dyspnea ARDS, acute respiratory distress syndrome; BOOP, bronchiolitis obliterans organizing pneumonia treated cancer patients (Box 14.3). As discussed above, immune-mediated or hypersensitivity pneumonitis is now seen as a combined type III and type IV hypersensitivity reaction in a Th1/ Th17 response. It has also been suggested that early-onset organizing pneumonia is a hypersensitivity reaction to the mAb, whereas the lateonset condition is either related to mAb toxicity or to immune system restoration. ARDS symptoms appearing within a few hours of infusion may be a manifestation of CRS (Sect. 14.2.2.6) or tumor lysis syndrome (TLS) (Sect. 14.2.2.7) with no relationship to hypersensitivity although ARDS has also been linked to release of proinflammatory cytokines. Of the 36 mAbs currently approved for anticancer therapy (at April 2020), rituximab, trastuzumab, alemtuzumab, and panitumumab provoke the biggest range of pulmonary adverse events.

Cardiac adverse events have occurred with at least 13 of the approved mAbs used for cancer therapy (Table 14 .5). Induced events are wide ranging and include decreased left ventricular ejection fraction (LVEF), cardiac arrhythmias, angina, supraventricular arrhythmia in some lymphoma patients, fatal myocardial infarction, heart failure, QT interval prolongation, and cardiopulmonary arrest and/or sudden death. Necitumumab carries an FDA black box warning for cardiopulmonary arrest. Decreases in LVEF are well-known for mAbs and other drugs that block HER2 activity, and this risk is increased in patients given anthracyclines (Chap. 15) or radiotherapy to the chest. Patients administered trastuzumab show a fourfold to sixfold elevation in the incidence of myocardial infarction, and this risk is highest when the mAb is given with an anthracycline.

These cutaneous reactions are not immunemediated, that is, they are not genuine hypersensi-tivities. Skin reactions after mAbs cetuximab and panitumumab often appear as a papulopustular eruption (sometimes less precisely called an acneiform rash), in a large proportion of patients (50- Patients receiving trastuzumab alone or in combination therapy show a fourfold to sixfold increase in the incidence of myocardial dysfunction 100%) and in a more severe form than seen with small molecule tyrosine kinase inhibitors such as erlotinib, gefitinib, and lapatinib (refer Sect. 14.1.1.3 and Fig. 14.4) . The skin lesions occurring after the mAbs consist of erythematous follicular papules that may evolve into pustules. The acneiform rash usually occurs a few days after administration of the mAb and reaches a maximum after 2-3 weeks. Eruptions tend to be confined to seborrheic regions of the face (Fig. 14.13) , scalp, neck, shoulders, and upper trunk (Figs. 14.14, 14.15, . These areas normally maintain their integrity via EGFR expressed in the epidermis, sebaceous glands, and hair follicles, but in the presence of inhibitors of EGFR, the epithelial barrier may be weakened allowing bacterial access and ultimately the development of the characteristic rash. EGFR inhibition together with radiotherapy may lead to radiation dermatitis enhancement, giving rise to wet or dry desquamation, necrosis, or cutaneous ulceration ( Fig. 14. 16d, e). Other adverse effects induced by mAbs targeted to EGFR include mucositis ( Fig. 14. 16f, g), xerosis, fissures (Fig. 14.16h) , paronychia (Fig. 14. 16i) including periungual granulation type (Fig. 14.17) , palmar-plantar rash, hair changes, hyperkeratosis, nail pyrogenic granuloma, and skin hyperpigmentation.

The FDA has issued boxed warnings for the possibility of serious or even fatal infusion reactions to ibritumomab vedotin, rituximab, alemtuzumab, cetuximab, panitumumab, trastuzumab, and dinutuximab and a general warning for the risk of infusion reactions during or following treatment with obinutuzumab, ofatumumab, brentuximab vedotin, bevacizumab, ramucirumab, pertuzumab, ado-trastuzumab emtansine, and siltuximab (Table 14 .4). Infusion reactions provoked by mAbs usually begin within hours of the initial infusion. Reactions are typically mild to moderate manifesting as "flu"-like symptoms of fever, chills, rigor, headache, nausea, asthenia, pruritus, and rash. In a small number of patients, severe, life-threatening symptoms common to type I IgE antibody-mediated anaphylaxis, in particular, hypotension, bronchospasm, cardiac arrest, and urticaria, may occur, usually during the first or second infusion. The similarity of the signs and symptoms can make it difficult to distinguish an infusion reaction from a true allergic hypersensitivity although IgE-mediated reactions generally have a faster and more severe onset, usually within minutes. Severe reactions have been reported for all, or almost all, the mAbs although some show a much higher incidence with the chimeric rituximab and humanized trastuzumab antibodies being the leading offenders. The incidence of reactions for cetuximab, another human-mouse chimera, is ~15-20% (grade 3-4, 3%); for trastuzumab, first infusion ~40% (grade 3-4, <1%); and for rituximab, first infusion ~77% (grade 3-4, 10%). Approximately 80% of fatal infusion reactions to rituximab occurred after the first infusion and 30% and 14% of patients still reacted after the fourth and eighth infusions, respectively. Even though trastuzumab is a humanized mAb, it induces a relatively high incidence of infusion reactions, but bevacizumab, another humanized antibody, shows a reaction incidence of only <3% (grade 3-4, 0.2%) which is similar to the fully humanized panitumumab (3%, grade 3-4, ~1%). Elotuzumab. recently approved for the treatment of multiple myeloma, provokes infusion reactions in a large proportion of patients and needs to be given with premedication. The mechanisms of mAb-induced infusion reactions are not yet fully understood. Cytokines, especially TNF and interleukins such as IL-6, may be involved since the symptoms they produce are similar in infusion and type I allergic reactions. An important finding was the observation that the severity of infusion reactions is related to the number of circulating lymphocytes. For example, a severe reaction is thought to require a high lymphocyte count. In the early years following the release of rituximab, the first mAb approved specifically for cancer therapy in 1997, a relationship between CRS in patients and high lymphocyte counts was observed after treatment with the mAb. Patients with lymphocyte counts greater than 50 × 10 9 /L experienced a severe cytokine-release syndrome shown by peaks in release of TNF and IL-6 90 min after infusion and accompanied by fever, chills, nausea, vomiting, hypotension, dyspnea, an increase in liver enzymes and prolongation of the prothrombin time. When used to treat B cell cancers, the frequency and severity of first-dose reactions to rituximab were shown to be dependent on the initial number of circulating tumor cells -patients with counts exceeding 50 × 10 9 /L experienced more adverse reactions than patients with lesser numbers of peripheral tumor cells. CRS may be seen after use of mAbs such as rituximab to treat malignant immune cells. It is thought that the systemic inflammatory response produced together with a high fever is a consequence of antibody binding to, and activating, the cells. The distinguishing features in the literature between CRS and severe infusion reactions are often not clear, and in many reported cases, the two designations may be interchangeable.

Depending on the anticancer agent used and the tumor load, within 48-72 h of starting therapy, large numbers of malignant cells may be destroyed in a short time resulting in hyperkalemia, hypercalcemia, hyperphosphatemia, and hyperuricemia. Especially in patients with high tumor load, this can produce profound ionic imbalances in potassium, calcium phosphate, and uric acid and progress to acute renal failure, cardiac arrhythmias, seizures, and death. Known as tumor lysis syndrome (TLS) and, unlike CRS, the response is easy to distinguish from type I immediate hypersensitivity reactions. TLS usually occurs in patients with leukemias and high-grade lymphomas and is rarely seen in association with solid tumors. The syndrome is well-known to occur with the use of the CD20-targeted mAbs and brentuximab vedotin targeted to CD30, but the reaction elicited by rituximab appears to be somewhat atypical and remains to be further characterized. The FDA has issued a TLS boxed warning for rituximab and warnings and precautions for obinutuzumab, brentuximab vedotin, blinatumomab, and polatuzumab vedotin-piiq (Table 14 .4).

Capillary leak syndrome (CLS), also known as systemic capillary leak syndrome, vascular leak syndrome, or Clarkson's disease, manifests as an increase in body weight, malaise, weakness, and sometimes abdominal pain, myalgia, pyrexia, vomiting, and diarrhea. Symptoms are variable and causes not well understood. An example of the condition may be seen following infusion of interleukin (IL)-2 for metastatic cancer. Within 24 h there is an increase in vascular permeability accompanied by extravasation of fluids and proteins resulting in peripheral and interstitial edema, pleural and pericardial effusions, ascites, and, in severe form, pulmonary and cardiovascular failure. Complications such as renal failure, stroke, ischemia, deep vein thrombosis, and rhabdomyolysis may occur. Erythematous cutaneous eruptions that often accompany the syndrome may be induced by cytokine activation of endothelial cells, and it has been suggested that these cells may have a role in the events underlying the syndrome. Monoclonal antibodies implicated in CLS include bevacizumab and dinutuximab.

Systemic inflammatory response syndrome (SIRS) is a serious systemic inflammatory disorder related to sepsis with the potential to cause organ dysfunction and failure. It may be caused by an infection or variety of noninfectious stimuli such as ischemia, trauma, pancreatitis, hemorrhage, adrenal insufficiency, anaphylaxis, or therapy, including treatments with biologic agents. SIRS may be diagnosed on the basis of two or more manifestations related to body temperature, heart rate, tachypnea, and white blood cell count. SIRS without infection may involve renal failure, deep vein thrombosis, disseminated intravascular coagulation, gastrointestinal bleeding, anemia, and hyperglycemia. In the early events in SIRS following trauma, infection, or other relevant stimuli, an inflammatory cascade is activated producing a multitude of cytokines, in particular, the proinflammatory cytokines IL-1, TNF, IL-6, IL-8, and IFN gamma. Infections stimulate the release of more TNF which in turn leads to more IL-6 and IL-8 and a higher rate of fever than is seen with trauma-induced SIRS. SIRS has been reported following infusion of catumaxomab and eculizumab.

The polyomavirus JC virus which persists asymptomatically in about one third of the population causes progressive multifocal leukoencephalopathy (PML) in severely immunodeficient individuals such as transplant and AIDS patients. PML is a progressive, usually fatal, disease resembling multiple sclerosis in which the myelin sheath of nerve cells is destroyed affecting nerve transmission. Although rare, the disease is occasionally seen after administration of some mAbs directed to B cells, in particular, rituximab, obinutuzumab, and brentuximab vedotin, and there are currently FDA boxed warnings for potentially fatal PML in patients treated with these mAbs and a warning for ofatumumab and polatuzumab vedotin-piiq (Table 14 .4). In 2009, 57 cases of PML following rituximab therapy in HIV-negative patients were reported. A 2010 report of the WHO Collaborating Centre for International Drug Monitoring Adverse Event Data Bank revealed that rituximab was responsible for 114 of 182 cases of PML.

• Specific targeting of tumor cells without inflicting collateral damage on normal healthy cells has been, and remains, a long-standing aim in cancer therapy. In what has been the mainstay of therapy, the administration of small cytotoxic molecules used with, or without, radiation therapy to kill rapidly dividing cells, often adversely affects normal, healthy cells such as mucosal lining cells and those in the bone marrow and hair follicles. • Here, targeted drugs have been divided into the natural or synthetic "small" molecules (i.e., generally MW ≤ 1 kDa; often called "chemotherapy" drugs) and the biologics.

• Effective targeting of tumor cells without accompanying toxicity has started to be realized with the introduction of signal transduction therapies and mAbs. • Signal transduction involves the utilization of biochemically induced signals generated by a range of large and small molecules such as growth factors, neurotransmitters, hormones, cytokines, chemokines, and ATP, to produce a wide variety of cell responses like cell division, metabolic changes, gene expression, and cell death. • The first signaling proteins to be utilized as targets for a new generation of unique anticancer drugs were protein kinases. Kinases transfer a γ-phosphate group (PO 3 2− ) from adenosine triphosphate to the hydroxyl group of tyrosine on signal transduction molecules (proteins), thus maintaining cellular functions. • Overexpression, dysregulation, and mutations of protein kinases involve them in the pathogenesis of many diseases including an association with oncogenesis. • At March 2019, the US FDA had approved 48 small molecule protein kinase inhibitors. • The Philadelphia translocation t(9;22) (q34;q11) or Philadelphia chromosome is a chromosomal defect resulting in gene fusion of the BCR and ABL genes. The resultant fusion gene is the BCR-ABL oncogene. The Philadelphia chromosome is a cytogenetic abnormality seen in 95% of chronic myeloid leukemia patients and 15-30% of adults with acute lymphoblastic leukemia. • The drug imatinib mesylate which inhibits both the ABL and BCR-ABL tyrosine kinases has been successful in treating chronic myeloid leukemia. • In addition to imatinib, some inhibitors of receptor tyrosine kinases targeting epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptors (VEGFR), and platelet-derived growth factor receptors (PDGFR) have been found to have antitumor and/or other activities. • For most of the tyrosine kinase inhibitors targeting the EGFR, papulopustular rash, handfoot skin reaction, pigmentary changes, xerosis, pruritus, and mouth, hair, scalp and nail abnormalities are the primary adverse events. • Imatinib is generally well tolerated especially when compared to most cytotoxic chemotherapies. Patients receiving standard-dose imatinib therapy in the chronic phase of chronic myeloid leukemia experience neutropenia in 35-45% of cases, thrombocytopenia in 20%, and anemia in 10% of cases.

• Although most cutaneous reactions to imatinib are mild and dose dependent, severe reactions such as SJS, exfoliative dermatitis, TEN, AGEP, DRESS, and lichenoid eruptions have been reported. • Gefitinib and erlotinib are EGFR inhibitors, inhibiting the receptor's tyrosine kinase domain by binding to the ATP-binding site of the enzyme. EGFR is overexpressed by the cells of some cancers such as lung and breast leading to uncontrolled cell proliferation. • The most frequent adverse reactions to gefitinib are diarrhea and skin reactions. The main adverse responses to erlotinib include rash, diarrhea, anorexia, ocular effects, and stomatitis. The FDA has referred to rare serious gastrointestinal, skin, and ocular disorders in some patients taking erlotinib. • As with other tyrosine kinase inhibitors, papulopustular rash, hand-foot skin reaction, and pigmentary changes are commonly seen with gefitinib and erlotinib. • Inhibition of the EGFR in skin often produces xerosis, skin fissures, nail alterations, paronychia, periungual ulcers, and pruritus. • Bortezomib, an N-protected dipeptide that contains a boron atom, inhibits proteasomes by binding via the boron atom to the catalytic site of the 26S proteasome with high affinity. This ultimately leads to the killing of multiple myeloma cells. • Gastrointestinal symptoms, thrombocytopenia, peripheral neuropathy, and neuropathic pain are the most common side effects of bortezomib. Adverse cutaneous reactions to the drug are numerous -rash is frequently reported in more than 10% of patients. • Cutaneous adverse drug reactions to bortezomib include Sweet's syndrome, ulceration, leukocytoclastic vasculitis, morbilliform exan-thema, folliculitis-like rash, erythematous nodules and plaques, and perivascular dermatitis. • Carfilzomib, a tetrapeptide epoxyketone, is structurally and mechanistically different to bortezomib. • Adverse reactions to carfilzomib include pulmonary hypertension, dyspnea, cardiac toxicities, cytopenias, infusion reactions, venous thrombosis, hemorrhage, tumor lysis syndrome, hepatotoxicity, posterior reversible encephalopathy syndrome, acute renal failure, rash, and urticaria. • Like bortezomib, ixazomib (MLN9708) is also a peptide boronate, but it is orally active with a shorter half-life and shows greater tissue penetration. FDA warnings and precautions for the drug relate to thrombocytopenia, gastrointestinal toxicities, peripheral neuropathy, hepatotoxicity, and cutaneous reactions. • Other promising proteosome inhibitors are the γ-lactam-β-lactone bicyclic marizomib and orally active oprozomib which shows similarities to carfilzomib and bortezomib. • Serine/threonine mTOR kinase belongs to the phosphoinositide 3-kinase (PIK3)-related family. mTOR inhibitors (e.g., everolimus), are associated with a considerable number of adverse events including interstitial lung disease, mucositis, hyperglycemia, new-onset diabetes mellitus, hyperlipidemia with increased levels of cholesterol and triglycerides, and reproduction effects. • Histone deacetylase inhibitors (HDACIs) lead to differentiation, cell-cycle arrest and inhibition of migration, invasion, and angiogenesis in many different cancer cells. • Myelosuppression involving thrombocytopenia, leukopenia, and anemia induced by romidepsin, vorinostat, belinostat, and panobinostat HDACIs is a frequent and often severe adverse event sometimes leading to serious hemorrhage and infection. Cardiac effects may occur, especially with QTc prolongation induced by vorinostat, and panobinostat has an FDA Boxed Warning for diarrhea. • Expression of the PML/RARΑ oncoprotein is diagnostic of promyelocytic leukemia (PML) and is downregulated in response to all-trans retinoic acid (tRA; ATRA; tretinoin). Approved for PML cases resistant to tRA, arsenic trioxide targets the PML moiety of PML/RARA protein. • Retinoic acid syndrome is a potentially fatal side effect of acute PML. The syndrome occurs in about one quarter of acute promyelocytic leukemia patients treated with tRA and/or arsenic trioxide. Symptoms include fever, hypotension, weight gain, dyspnea with pulmonary infiltrates, pleuropericardial effusion, and renal failure. The syndrome is called differentiation syndrome since it occurs in patients previously treated with arsenic trioxide but not in patients treated with tRA for other disorders.

• The synthetic retinoic X receptor (RXR) agonist bexarotene, an oral retinoid therapy, is approved for the treatment of cutaneous T cell lymphoma. Side effects include hypothyroidism, hypertriglyceridemia, and hypercholesterolemia. • Hormone therapy for some cancers such as breast and prostate can be as potent and effective as many other cancer treatments. Symptoms induced by the administered hormone or analog may cause nausea, muscle and joint pain, hair loss, blood clots, and an increased risk of some cancers, for example, endometrial cancer and cancer of the uterus. Side effects in males include tiredness, hot flashes, nausea, loss of sex drive, impotence, and breast tenderness. • At April 2020, of the currently approved 88 mAbs, 36 or 41% are indicated for the treatment of human cancers covering hematologic, solid tumor, and cutaneous malignancies. • In achieving the wide and diverse coverage of a large variety of tumors, a range of different targets and mechanisms of action have been sought. Twenty-three different targets have been utilized so far. • Some targets are complementary to more than one mAb: CD20 is targeted by 4 mAbs, EGFR by 3, HER2 by 3, PD-L1 by 3, PD-1 by 2, D38 by 2, and CD22 by 2. • Mechanisms employing mAb-targeted therapies are predominately direct cytotoxic action against cancer cells, an effect on signaling Reactions typically manifest as "flu"-like symptoms. In a small number of patients, severe, life-threatening symptoms common to type I IgE antibody-mediated anaphylaxis are seen. The similarity of the symptoms can sometimes make it difficult to distinguish an infusion reaction from a true allergic hypersensitivity. • Cytokines may be involved in infusion reactions since the symptoms they produce (called cytokine-release syndrome (CRS)) resemble those seen in type I allergic reactions. The severity of such reactions is related to the number of circulating lymphocytes. The distinguishing features between CRS and severe infusion reactions are often not clear. • Depending on the anticancer agent used and the tumor load, large numbers of malignant cells may be destroyed in a short time resulting in hyperkalemia, hypercalcemia, hyperphosphatemia, and hyperuricemia. Known as tumor lysis syndrome (TLS) and, unlike CRS, the response is easy to distinguish from type I immediate hypersensitivity reactions. The FDA has issued a TLS boxed warning for rituximab and warnings and precautions for obinutuzumab, brentuximab vedotin, blinatumomab, and polatuzumab vedotin-piiq. • Capillary leak syndrome, also known as vascular leak syndrome, manifests as an increase in body weight, malaise, and weakness. Symptoms are variable and causes not well understood. Within 24 h there is an increase in vascular permeability, extravasation of fluids, and proteins resulting in peripheral and interstitial edema, pleural and pericardial effusions, ascites, and, in severe form, pulmonary and cardiovascular failure. Complications such as renal failure, stroke, ischemia, deep vein thrombosis, and rhabdomyolysis may occur. Endothelial cells and cytokine release may have a role in the events underlying the syndrome. The mAbs bevacizumab and dinutuximab have been implicated. • Systemic inflammatory response syndrome (SIRS) is a serious systemic inflammatory disorder related to sepsis with the potential to cause organ dysfunction and failure. It may be caused by an infection or variety of noninfectious stimuli such as ischemia, trauma, anaphylaxis, or therapy, including treatments with biologic agents. In the early events in SIRS, an inflammatory cascade is activated producing a multitude of cytokines, in particular, the proinflammatory cytokines IL-1, TNF, IL-6, IL-8, and IFN gamma. Monoclonal antibodies implicated include catumaxomab and eculizumab. • Caused by the polyomavirus JC virus which persists asymptomatically in about one third of the population, progressive multifocal leukoencephalopathy (PML) is a progressive, usually fatal, disease resembling multiple sclerosis in which the myelin sheath of nerve cells is destroyed affecting nerve transmission. The disease is occasionally seen after administration of some mAbs directed to B cells, in particular, rituximab, obinutuzumab, and brentuximab vedotin.

Role of tyrosine kinase inhibitors in cancer therapy

Adverse events to monoclonal antibodies used for cancer therapy: focus on hypersensitivity responses

Safety of biologics therapy. Monoclonal antibodies, cytokines, fusion proteins, hormones, enzymes, coagulation proteins, vaccines, botulinum toxins

Adverse events to nontargeted and targeted chemotherapeutic agents. Emphasis on hypersensitivity responses

Adverse reactions to targeted and non-targeted chemotherapeutic drugs with emphasis on hypersensitivity responses and the invasive metastatic switch

Development of the National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE)

Kinasetargeted cancer therapies: progress, challenges and future directions

Mechanism of action of CD20 antibodies

Releasing the brake on the immune system: the PD-1 strategy for hematologic malignancies

Antibody-drug conjugates for cancer

Managing premedications and the risk for reactions to infusional monoclonal antibody therapy

Translation of the Philadelphia chromosome into therapy for CML

Narrative review: the systemic capillary leak syndrome

Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition

The tumor lysis syndrome

Retinoic acid actions through mammalian nuclear receptors

Monoclonal antibodies -a new era in the treatment of multiple myeloma

Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia

Strategies for the management of adverse events associated with mTOR inhibitors

Antibodies to watch in 2020

Antibodies to watch in 2019

Tolerability and safety of rituximab (MabThera®)

Proteasome inhibitors: an expanding army attacking a unique target

Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox

Signal transduction therapy of cancer

Epidermal growth factor receptor inhibitor -associated cutaneous toxicities: An evolving paradigm in clinical management

Proteasome inhibitors in multiple myeloma: ten years later

Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway

The ins and outs of Bcr-Abl inhibition

Properties of FDA-approved small molecule protein kinase inhibitors

Safety and tolerability of histone deacetylase (HDAC) inhibitors in oncology

The proteasome: overview of structure and functions

Proteosome inhibitors

Antibody-drug conjugates: recent advances in conjugation and linker chemistries

Hyperkeratotic skin adverse events induced by anticancer treatments: a comprehensive review

Exploiting the cancer genome: strategies for the discovery and clinical development of targeted molecular therapeutics

pathways, or immune modulatory effects leading to the indirect destruction of cancer cells.• A direct cytotoxic action can be achieved by using an antibody-drug conjugate (ADC), whereby cell killing is effected by an attached bioactive payload of a potentially lethal toxin, drug, cytokine, or radionuclide. Adotrastuzumab emtansine, brentuximab vedotin, ibritumomab tiuxetan, inotuzumab ozogamicin, moxetumomab pasudotox-tdfk, gemtuzumab ozogamicin, polatuzumab vedotin-piiq, and sacituzumab govitecan-hziv are 8 currently approved ADCs. • Examples of cell-destructive immune modulatory effects include antibody-dependent cell cytotoxicity (ADCC) and modulation of immune checkpoints by the targeting of inhibitory pathways regulating signaling between T cells and antigen-presenting cells. Monoclonal antibody checkpoint inhibitors are ipilimumab, nivolumab, pembrolizumab, cemiplimab-rwlc, atezolizumab, avelumab, and durvalumab. • Cytopenias are a well-known side effect of mAbs therapy, but the underlying mechanisms frequently remain unexplored, and types II and III hypersensitivities induced by the antibodies may be underdiagnosed and underreported. Boxed warnings have been issued for the risk of severe cytopenias with ibritumomab tiuxetan and alemtuzumab, while general warnings and precautions are set down for obinutuzumab, ofatumumab, brentuximab vedotin, trastuzumab, and ado-trastuzumab emtansine. • Apart from abciximab, targeted to platelet glycoprotein GP IIb/IIIa and not used to treat cancer, there appears to be a dearth of convincing evidence for the involvement of anticancer mAbs in type II hypersensitivity reactions. Rituximab-induced neutropenia is a suspected example of a mAb-induced type II hypersensitivity. • With some mAbs, type III hypersensitivity serum sickness-like reactions are reported in up to 20% of treated patients. Cases of mAb-induced cutaneous vasculitis during treatment also occur, for example, with adalimumab. • The checkpoint inhibitors provoke a number of immune-mediated reactions. Perhaps the most dangerous is immune-mediated, or hypersensitivity, pneumonitis, a combined type III and type IV hypersensitivity reaction. Anti-PD-1 and anti-PD-L1 therapy may induce immunemediated colitis, hepatitis, endocrinopathies, nephritis, and thyroid reactions. • Monoclonal antibody-induced type IV hypersensitivity reactions of the skin include allergic contact dermatitis, psoriasis, maculopapular exanthema, fixed drug eruption, acute generalized exanthematous pustulosis, erythema multiforme, DRESS, and cutaneous bullous toxidermias such as SJS and TEN. Panitumumab carries a black box warning for dermatologic toxicity. Cutaneous acneiform rash reactions that are not genuine hypersensitivities are seen with the EGFRtargeted mAbs cetuximab, panitumumab, and necitumumab.• At least 14 of the currently approved mAbs for cancer therapy have been implicated in some form of pulmonary toxicity in treated cancer patients, but rituximab, trastuzumab, alemtuzumab, and panitumumab provoke the biggest range of pulmonary adverse events. • Cardiac adverse events have occurred with at least 13 of the approved mAbs used for cancer therapy. Necitumumab carries an FDA black box warning for cardiopulmonary arrest. Decreases in LVEF are well-known for mAbs that block HER2 activity. The risk is increased in patients given anthracyclines or radiotherapy. • Skin reactions after cetuximab and panitumumab often appear as a papulopustular eruption usually confined to seborrheic regions of the face, scalp, neck, shoulders, and upper trunk. Other adverse effects induced by mAbs targeted to EGFR include mucositis, xerosis, fissures, paronychia, palmar-plantar rash, hair changes, hyperkeratosis, nail pyrogenic granuloma, and skin hyperpigmentation. • Infusion reactions provoked by mAbs usually begin within hours of the initial infusion.