Background    ‘Targeted cancer therapy’ is an umbrella term for a diverse group of newer antineoplastic agents. Fast Fact #276 focused on tyrosine kinase inhibitors (TKIs). This Fast Fact focuses on monoclonal antibodies (mAbs), the second major group of targeted cancer agents.

Monoclonal antibody development     Antibodies are generated from a single clone of immune cells, and are directed against one specific epitope on the surface of cancer cells. MAbs can be derived from mouse, human, or hybrid elements; newer developments favor human-only in order to minimize anti-murine inflammatory response by the patient and to maximize target antigen specificity (1-4). MAb nomenclature reflects its derivation: -omab (entirely murine derived); -ximab (human-murine chimera); -zumab (up to 90% human); -mumab (entirely human). Since the first approval of rituximab as cancer therapy targeting CD 20 in 1997, the development of monoclonal antibodies targeting different antigens have been progressing fast. The recent FDA approvals of nivolumab and pembrolizumab highlight the fervor for mAbs targeting immune checkpoints to regulate endogenous antitumor activity.

Modes of action of monoclonal antibodies    Unlike TKIs, the large size of mAbs necessitates they have activity on cell surfaces where they can induce immune responses against targeted cancer cells or interfere with proteins necessary for cell growth. Targeted activity may be enhanced by linking “naked” mAbs to other agents, including cytotoxic drugs or radioisotopes. They can be used as single agents, or combined with chemotherapy or hormonal therapy.

Side effects and complications of mAbs    Common side effects of mAbs include allergic reactions, infusion reactions, flu-like symptoms, pneumonitis, gastrointestinal distress with nausea, vomiting and/or diarrhea, hypotension, skin rashes, and cytopenias. Premedicating patients with acetaminophen, antihistamines, steroids, and non-steroidal anti-inflammatory drugs prior to mAb administration is a standard part of preventative treatment (5). Important drug-specific side effects are outlined below (6,7).

Management of specific side-effects

Cardiovascular:

• Congestive heart failure (CHF): Monitoring cardiac function by close physical examination, laboratory assessment, EKGs and serial echocardiograms is indicated with some of the mAbs (e.g. trastuzumab) and in symptomatic patients. Standard treatment of CHF with ACE inhibitors, beta-blockers, diuretics and/or aldosterone receptor blockers is indicated. A left ventricular ejection fraction below 40% usually precludes starting or continuing many mAbs.
• Hypertension: As with TKIs, mild to moderate hypertension requires only observation. For moderate to severe hypertension, no specific drug guidelines exist and the hypertension is treated empirically. If hypertension cannot be managed, mAb treatment is discontinued.
• Thromboembolism: A complication of VEGF mAb therapy (e.g. bevacizumab), risk factors include age >65 and a history of thromboembolic events. Some clinicians empirically use aspirin to try to prevent thromboembolism (8).

Dermatologic: skin toxicities from EGFR monoclonal antibodies (e.g. panitumumab, cetuximab) are often more severe than from TKIs. However, evidence-based prevention or management guidelines do not exist. (9) Tetracyclines are often employed for management of acneiform rash.

Hypersensitivity reactions: The majority of these reactions are mild and occur within 30 minutes to two hours after the first or second exposure of the agent. Rituximab, alemtuzumab, trastuzumab and cetuximab are particularly associated with infusion reactions.  Symptoms are felt to be secondary to cytokine release and may include fevers, rigors, flushing, chest discomfort, skin rashes, nausea or diarrhea.  Immediate discontinuation of the infusion and administration of oxygen, intravenous normal saline to prevent/treat hypotension and intravenous antihistamines are indicated. Subcutaneous or intravenous epinephrine, inhaled beta-agonists to address potential bronchospasms and intravenous corticosteroids may be required in severe cases or anaphylaxis.

References

1. Köhler G and Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975; 256:495-497.
2. Carter P. Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer. 2001; 1:118-129.
3. Beck A, Wurch T, Corvaia N. Therapeutic antibodies and derivatives: from the bench to the clinic. Curr Pharm Biotechnol. 2008; 9:421-422.
4. Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov. 2010; 9:767-774.
5. Vultaggio A, Maggi E and Matucci A. Immediate adverse reactions to biologicals: From pathogenic mechanisms to prophylactic management. Curr Opin Allergy Clin Immunol 2011; 11:262-268.
6. Klastersky, J. Adverse effects of the humanized antibodies used as cancer therapeutics. Curr Op Oncol. 2006; 18(4):316-320.
7. Myskowski PL, Halpern AC. Cutaneous adverse reactions to therapeutic monoclonal antibodies for cancer. Curr Allergy Asthma Rep. 2008; 8(1):63-8.
8. Svoboda M, Poprach A, Dobes S, Kiss I, Vyzula R. Cardiac toxicity of targeted therapies used in the treatment for solid tumours: a review. Cardiovasc Toxicol. 2012; 12(3):191-207.
9. Baas JM, Krens LL, Guchelaar HJ, et al. Recommendations on management of EGFR inhibitor-induced skin toxicity: a systematic review. Cancer Treat Rev. 2012; 38(5):505-14. doi: 10.1016/j.ctrv.2011.09.004
10. Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
11. Borghaei H, Paz-Ares L, Horn L et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627-39.
12. Motzer RJ, Escudier E, McDermott DF et al. Nivolumab versus Everolimus in advanced renal cell carcinoma, N Engl J Med 2015;372:1803-13.
13. Keytruda package insert http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
14. Drew M Pardoll. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer 12 2012: 252-64.

Authors’ Affiliation: National Institutes of Health Clinical Center, Bethesda, MD.

Conflict of Interest Disclosure: The authors have disclosed no relevant conficts of interest.

Version History: First electronically published in December 2013; re-copy-edited in December 2015 by Minhee Kang Pharm D.