Considerations for Monoclonal Antibodies in Oral Healthcare

Comprising a large and fast-growing group of medications with diverse therapeutic targets, monoclonal antibodies (mAbs) have a wide variety of current and potential applications. The first mAb was generated in 1975, and the first mAb muro­monab-CD3, a mouse antibody used to prevent kidney transplant rejection, was approved by the U.S. Food and Drug Administration (FDA) in 1986.¹ Progress in biotechnology allowed for development of partially and then fully human mAbs, which reduce the risk of immune response and permit wider use.^1,2 This field has progressively grown since its introduction: 2018 had the greatest number of FDA approvals — 12 — and, by August 2020, five new mAbs were approved, with 17 more under review.^3,4

Along with vaccines, blood/​blood components, tissues, cells and other substances of biological origin, mAbs are biologics produced by complex biotechnological methods overseen by the FDA. Like typical chemotherapeutic agents, biological products undergo the rigorous process of approval, monitoring, and post-market surveillance, ensuring their safety and effectiveness, and helping to detect adverse reactions not identified during clinical trials.

Yet, despite their generally good tolerability and specificity to the intended cells and tissues defined as “targeted therapies,” mAbs are not without adverse effects, including oral and perioral — some severe enough to warrant discontinuation of therapy.^5,6 As the variety, number and therapeutic indications for mAbs continue to increase,^3,7,8 the chance of encountering dental patients using these biologics (or the growing number of their generic versions, known as biosimilar products) will grow. Understanding the conditions being treated and their manifestations, as well as therapeutic and adverse reactions to the medication regimens — along with interactions with other drugs and supplements — is vital to providing safe treatment. Awareness of oral and perioral adverse reactions to mAbs will aid differential diagnosis, while detailed communication with prescribing providers will help oral health professionals determine appropriate care.

DEFINITION OF MONOCLONAL ANTIBODIES

Antibodies are immunoglobulin (Ig) molecules, which are proteins of five different classes — IgA, IgD, IgE, IgG and IgM — produced by the B-lymphocytes as a defense mechanism against foreign substances (e.g., microorganisms or allergens) and those produced by the host (such as cancer cells, or normal healthy cells in the case of autoimmune reactions). In a typical immune reaction, the immunoglobulins are produced by many different B-cells, with only slight differences in their binding site or affinity to the antigen; these immunoglobulins are called polyclonal. In contrast, monoclonal immunoglobulins are all produced by a single B-lymphocyte clone with identical structures and antigen-binding characteristics. Structurally, mAbs are IgG proteins and are the most abundant and smallest of the Igs, with a molecular weight of ~150 kDa. There are four IgG subclasses in humans.⁷ Consisting of two pairs of heavy and light chains, mAbs have constant and variable regions (Figure 1). The unique hypervariable region at the end of variable region determines mAb specificity and interaction with the target site of the antigen. Immunogenicity of mAbs decreases depending on the origin of the constant and variable/​hypervariable regions, from fully murine to chimeric (~33% mouse), humanized (~90% human), and fully human.^2,6,9

The large size and complex molecular structure of mAbs may inhibit their distribution to the sites of action and, thus, their efficacy. To overcome this, smaller fragments (Fabs) consisting of the mAbs’ variable site and portions of light and heavy chains have been developed. These fragment antibodies and single-chain antibodies improve pharmacokinetic properties and efficiency of dissemination of the drugs to their targets.^1,10 In addition, due to their “lock and key” specificity, mAbs can be used for targeted delivery of other drug molecules to the intended cells by creating conjugates of the drug/​toxin and appropriate mAb.^1,9,10 The conjugates of mAbs with cytotoxic drugs or radionuclides (Table 1), enzymes, and plant/​bacterial toxins ensure their direct delivery to the intended targets and minimize potential damage to healthy cells.⁹

In therapy, mAbs exert several mechanisms of action and some drugs work by more than one mode, triggering multiple receptor and cellular interactions.^6,9 Neutralization of the target can be accomplished by mAbs blocking action against the receptor or its binding molecule, referred to as receptor or ligand antagonism. Examples of mAbs that work by blocking include adalimumab, which targets tissue necrosis factor involved in inflammation (used in treating rheumatoid arthritis, Crohn’s disease and psoriasis), and omalizumab, which targets IgG produced in allergic reactions and asthma (used in long-term treatment of severe asthma attacks).⁹

This mechanism of action is also used in reversing drug actions. For instance, Fab idarucizumab binds to the oral anticoagulant dabigatran, neutralizing it in case of bleeding. It is the first reversal agent for the novel oral anticoagulants, whose availability allows for a wider use of anticoagulants, such as dabigatran as a safer alternative to warfarin.¹¹ Finally, neutralization is the mechanism of action for the treatment and prophylaxis of viral and bacterial infections, targeting agents such as respiratory syncitial virus, human immunodeficiency virus, rabies virus, Clostridium difficile and Bacillus anthrasis (Table 1).^3,4,12 The COVID-19 pandemic also prompted robust investigation into the potential use of mAbs against SARS-CoV-2 by blocking the interaction of the virus’ spike proteins with key cellular receptors in human tissues.¹³

Blocking the target signaling pathway is the mechanism of action for many mAbs used in cancer treatment. Upon binding to the target tumor cell receptor, mAbs will affect the downstream signaling and intracellular messaging, resulting in inhibition of cell growth or proliferation, or induction of the programmed cell’s death (apoptosis).⁹ However, this action is not limited to cancer treatment. Three mAbs have been approved for migraine prevention (erenumab, galcanezumab and eptinezumab) since 2018. Each of these agents targets calcitonine gene-related peptide receptors located on the neuron cell surface, whose activation induces an intracellular cascade, leading to propagation of the pain impulse.^4,14

Following their binding to the target cell, mAbs can recruit immune cells to generate antibody-dependent cell-mediated cytotoxicity (ADCC). This mechanism, as well as similar immune-mediated complement-dependent cytotoxicity (CDC) reactions, leads to the death of the target cell via lysis.⁹ These interactions involving the host immune system usually work together with neutralizing function of the mAbs, and are used in cancer immunotherapies. Cetuximab is such a drug, targeting epidermal growth factor receptors (EGFR) expressed on the surface of cancer cells. It uses all three modes, blocking, ADCC and CDC, in treatment of colorectal and head and neck cancers.⁹

Because their oral bioavailability is very low, mAb drugs are administered by subcutaneous, intramuscular or intravenous injection.^7,15 Subcutaneous administration is used most frequently due to its convenience and possibility of self-adminstration.⁷ As mAbs are large proteins with heavy molecular sizes, they have a slower distribution, with peak plasma concentrations usually three to seven days post-administration. Unlike most typical small-molecule drugs, mAbs are not eliminated by the kidneys. Instead, they are degraded to peptides/​amino acids by intracellular lysosomal metabolism and either recycled for protein synthesis or eliminated though the kidneys as smaller molecules.³ This explains their longer half-lives and provides an advantage of administration on a weekly, biweekly or monthly schedule.^7,15

THERAPEUTIC INDICATIONS

The number and variety of therapeutic applications of mAbs continue to grow with the identification of cellular and receptor targets that have been considered undruggable by traditional chemotherapeutics.¹⁰ For many diseases, such as rheumatoid arthritis, mAbs are the standard of care, while in cancer therapy they are often used in conjunction with traditional treatment, such as radiation and chemotherapy.^10,12,16 For conditions marked by intense pain (such as migraine), or painful unsightly lesions (as in psoriasis), mAb immunotherapies can improve quality of life by reducing the number and intensity of episodes or improving appearance.^14,17

ADVERSE EFFECTS AND REACTIONS

Generally, due to their high specificity to intended targets, mAbs are well tolerated and adverse effects are typically mild — ranging from skin reactions at the site of injection to flu-like symptoms.^3,6,9 However, some patients experience reactions severe enough to necessitate drug discontinuation, and some are life threatening.⁶ Most severe acute reactions following mAbs administration include immediate or delayed-onset anaphylaxis (type I hypersensitivity), serum sickness (type III hypersensitivity reaction), tumor lysis syndrome and cytokine release syndrome (CRS), also known as cytokine storm. In fact, mAbs can provoke all four types of hypersensitivity reactions.¹⁸ Immune-mediated reactions to mAbs are not entirely preventable with reduction of animal-derived antibody sequence. An immune response against fully human mAbs can also be initiated due to differences in protein sequence.^6,18 This risk is higher in chimeric and humanized mAbs; for example, omalizumab — used to treat acute asthma attacks — can trigger anaphylactic reactions in 0.1% to 0.2% of patients.⁶ Tumor lysis syndrome is a life-threatening reaction to mAbs used in antineoplastic therapy, and is directly related to destroying cancer cells whose lysis generates a systemic inflammatory response. It can lead to overwhelming ionic imbalance and progress to acute renal failure, cardiac arrhythmias and death.¹⁸

Finally, CRS is an acute complication resulting from the release of various pro-inflammatory cytokines. In one report, systemic inflammatory reaction to the massive cytokine release progressed from headache, malaise, nausea and hypotension to lung injury, renal failure and disseminated intravascular coagulation, followed by cardiovascular shock and acute respiratory distress syndrome. The potential consequences of CRS highlight the risks associated with mAbs and led to changes in determining the initial doses of mAbs in human studies.⁶ Still, CRS is not entirely preventable and poses a serious potential complication.

Infectious diseases due to immunosuppression associated with mAb therapies can be prevented, but not eliminated, by screening prior to mAb therapy. A reactivation of latent human polyomavirus-2 in the central nervous system can lead to progressive multifocal leukoencephalopathy — a rapidly progressing demyelinating disease that resembles multiple sclerosis and is usually fatal.¹

Thrombocytopenia is another drug-induced acute immune complication that can be caused by mAbs. Its prevalence increases with repeat administration, and it can be fatal.^6,18 As immunomodulating agents, mAbs can also cause autoimmune conditions, such as lupus-like syndromes, thyroid disease and autoimmune colitis, though these are rare.^6,18 Although used as therapeutic agents in oncology,^9,12,18 some mAbs are associated with increased cancer risk.⁶ The role of the immune system in identifying and targeting malignant cells and the immunosuppressive mechanism of action of mAbs help explain this association.^3,6

Other adverse reactions can be directly related to the intended function of mAbs. For example, bevacizumab — which targets vascular endothelial growth factor (VEGF) controlling development of blood vessels — blocks VEGF function in malignant tumors and is used in the treatment of breast, lung, colorectal, and other cancers. However, its effect is beyond the tumor, restricting angiogenesis in healthy tissues as well.⁹ Similarly, cetuximab and panitumumab, used in treating solid tumors, block EGFRs located in the epithelial tissues. Since these agents block epidermal growth factor pathways in healthy tissues as well as tumors, they commonly cause negative dermatological and mucosal — including oral/​perioral — effects.^6,19 When administered with radiation or chemotherapy, these mAbs can exacerbate mucositis associated with those therapies.¹⁹

ORAL/PERIORAL ADVERSE EFFECTS AND COMPLICATIONS

Some mAbs cause less frequent but concerning complications, such as oral lichenoid drug-induced reactions or eruptions (OLDRs)^20–24 and medication-related osteonecrosis of the jaw (MRONJ).^25,26 Clinically, OLDRs are indistinguishable from idiopathic lichen planus, and histological differences are not definitive.^22,24 Painful OLDRs may be unilateral and found in less typical locations (e.g., labial or palatal mucosa) than lichen planus (often found in bilateral buccal mucosa or the tongue).²² They can appear from several days to weeks into treatment with mAbs.^20–23 Differential diagnosis is based primarily on a thorough medical/​drug history, and improvement or disappearance of lesions following drug discontinuation confirms the diagnosis.^22,24 However, this must be done in consultation with the prescribing physician and only if an acceptable substitute drug is available. Topical or systemic corticosteroids may be prescribed to facilitate healing, and the complete disappearance of the lesions may take weeks or months after drug discontinuation.^20,21,23

The clinical presentation of MRONJ related to mAbs is no different from that caused by bisphosphonate use. Necrotic lesions most frequently appear on the mandible following surgery, tooth extractions, implant placement or spontaneously, from a few weeks to more than a year after beginning mAb therapy.²⁶ Several mAbs with different mechanisms of action have been associated with MRONJ, including denosumab used in osteoporosis prevention, bevacizumab used in cancer treatment, and adalimubab and rituximab used in the management of rheumatoid arthritis, psoriasis, ulcerative colitis, and other immune-mediated conditions (Table 1).^25,26 Pathogenesis of MRONJ in the case of denosumab and immunomodulatory mAbs is not well understood, while anti-VEGF agents affect the bone due to their inhibition of angiogenesis and reduction of vascularization of bone.²⁶ As there is no effective treatment for MRONJ, its prevention is key, and patients may be advised to complete dental/​periodontal treatments prior to initiation of immunotherapies or, if possible, postpone them.²⁶ As always, thorough evaluation of patients’ medication use and, if necessary, consultation with their medical providers will help in diagnosis and management of oral/​perioral complications.

CONCLUSION

Targeted immunotherapies with mAbs represent one of the fastest growing areas of drug development today. Oral health professionals’ understanding of their therapeutic indications and effects, as well as general and oral adverse effects of various mAbs, is key to providing comprehensive, collaborative patient care.

REFERENCES

1. Liu JKH. The history of monoclonal antibody development — progress, remaining challenges and future innovations. Ann Med Surg. 2014;3:113–116.
2. Van Hoecke L, Roose K. How mRNA therapeutics are entering the monoclonal antibody field. J Transl Med. 2019;17:54.
3. Castelli MS, McGonigle P, Hornby PJ. The pharmacology and therapeutic applications of monoclonal antibodies. Pharmacol Res Perspect. 2019;7:6.
4. The Antibody Society. Antibody Therapeutics Approved or in Regulatory Review in the EU or US. Available at: antibodysociety.org/​resources/​approved-antibodies. Accessed January 28, 2021.
5. U.S. Food and Drug Administration. What Are “Biologics?” Questions and Answers. Available at: fda.gov/​about-fda/​center-biologics-evaluation-and-research-cber/​what-are-biologics-questions-and-answers. Accessed January 28, 2021.
6. Hansel TT, Kropshofer H, Singer T, Mitchell JA, George AJ. The safety and side effects of monoclonal antibodies. Nat Rev Drug Discov. 2010;9:325–338.
7. Ovacik M, Lin K. Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development. Clin Transl Sci. 2018;11:540–552.
8. Kaplon H, Muralidharan M, Schneider Z, Reichert JM. Antibodies to watch in 2020. mAbs. 2020;12:1703531.
9.  Suzuki M, Kato C, Kato A. Therapeutic antibodies: their mechanisms of action and the pathological findings they induce in toxicity studies. J Toxicol Pathol. 2015;28:133–139.
10. Slastnikova TA, Ulasov AV, Rosenkranz AA, Sobolev AS. Targeted intracellular delivery of antibodies: the state of the art. Front Pharmacol. 2018;9:1208.
11. Jarrett JB, Gimbar RP. Idarucizumab (Praxbind) for Dabigatran (Pradaxa) anticoagulant reversal. Am Fam Physician. 2017;95:798–800.
12. Drewe E, Powell RJ. Clinically useful monoclonal antibodies in treatment. J Clin Pathol. 2002;55:81–85.
13. Marovich M, Mascola JR, Cohen MS. Monoclonal antibodies for prevention and treatment of COVID-19. JAMA. 2020;324:131–132.
14. American Migraine Foundation. CGRP Antibodies and Receptor Blockers for Migraine. Available at: americanmigrainefoundation.org/​resource-library/​cgrp-antibodies-and-receptor-blockers/​. Accessed January 28, 2021.
15. Keizer RJ, Huitema AD, Schellens JH, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:493–507.
16. Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov. 2010;9:767–774.
17. National Psoriasis Foundation. What Is Psoriasis, What Causes It and What Are Your Treatment Options? Available at: psoriasis.org/​about-psoriasis. Accessed January 28, 2021.
18. Baldo BA. Adverse events to monoclonal antibodies used for cancer therapy. Oncoimmunology. 2013;2:10.
19. Chmieliauskaite M, Stojanov I, Saraghi M, Pinto A. Oral adverse events associated with targeted cancer therapies. Gen Dent. 2018;66:26–31.
20. Kuten-Shorrer M, Hochberg EP, Woo SB. Lichenoid mucosal reaction to rituximab. Oncologist. 2014;19:e12–e13.
21. Lee M, Seetharamu N. An atypical presentation of lichen planus-like reaction from pembrolizumab. Case Rep Dermatol Med. 2019;2019:4065437.
22. Rice PJ, Hamburger J. Oral lichenoid drug eruptions: their recognition and management. Dent Update. 2002;29:442–447.
23. Thompson JM, Cohen LM, Yang CS, Kroumpouzos G. Severe, ulcerative, lichenoid mucositis associated with secukinumab. JAAD Case Rep. 2016;2:384–386.
24. Bariş E, Sengüven B, Tüzüner T, Gültekin SE. Oral lichenoid lesions related to drugs: review of clinicopathological features and differential diagnosis. Eur J Inflamm. 2014;12:217–225.
25. Lombard T, Neirinckx V, Rogister B, Gilon Y, Wislet S. Medication-related osteonecrosis of the jaw: new insights into molecular mechanisms and cellular therapeutic approaches. Stem Cells Int. 2016;2016:8768162.
26. Eguia A, Bagan L, Cardona F. Review and update on drugs related to the development of osteonecrosis of the jaw. Med Oral Patol Oral Cir Bucal. 2020;25:e71–e83.

From Decisions in Dentistry. March 2021;7(3):32–35.