Understanding potential exposure to monoclonal antibodies (mAb) informs the occupational risk assessment

Understanding the properties of monoclonal antibodies  

Monoclonal antibodies (mAb) are large, protein-based medicines with high target specificity and distinct pharmacological properties. Use of mAb has expanded significantly in recent years and they are now being used in most therapeutic areas, in both acute and community settings. Until recently, mAb could be easily identified by the –mab suffix at the end of their name. It is important to note that since 2022, monoclonal antibodies may also have the following suffixes -tug, -bart, -ment and -mig.  

Unlike small molecule medicines, mAb differ in their pharmacological and pharmacokinetic properties. mAb are proteins comprised of natural amino acids and their metabolism (catabolism into constituent amino acids) is well-defined. The primary clinical toxicity of mAb is due to their molecular pharmacology and not to in vivo production of reactive intermediates or toxic metabolites.  

The primary clinical toxicity of many mAb is due to exaggerated pharmacology related to blocking or enhancing the activities of the target molecule on the target cells or tissues. Toxicity can also result from binding to target antigen in tissues other than those necessary for therapeutic effect.  

Potential routes of exposure

For any substance to cause harm, exposure must first occur, therefore identifying potential routes of exposure is crucial to understanding the risks and implementing appropriate precautions. Our article about risk assessing the preparation of monoclonal antibodies provides more information.  

In practice, all currently licensed mAb for injection are supplied as closed systems in vials. This reduces the possibility of accidental exposure by any route during handling, when prepared according to the manufacturer’s instructions by competent professionals. Locally approved procedures for the preparation and administration of injectable medicines should also be designed to minimise risk of accidental exposure.

Potential routes of exposure in the event of accidental release are discussed later in this article.

Needlestick

In the event of a needlestick injury, small amounts of mAb may enter the systemic circulation. This is an unlikely route of exposure if Aseptic Non-Touch Technique (ANTT) and good practice guidance for prevention of needlestick injuries are followed.  

Topical or dermal

The risk of systemic absorption following topical exposure depends on molecular size.  Generally, molecules larger than 500 Daltons are not easily or rapidly absorbed through intact skin.  Additional consideration should be given to the risk to operators with damaged skin where the level of absorption may differ, or local irritation may occur.  

Overall, the risk of systemic absorption via the dermal route is considered low, especially if ANTT is used. This may involve the use of disposable gloves, depending on local policy.

Inhalation

The inhalation exposure risk is influenced by the  

  • formulation – a powder is more likely to be aerosolised than a liquid 
  • molecule size – the larger the molecule, the less likely it is to be absorbed 
  • the likelihood of systemic absorption by the lungs – mAb intended to have a biological impact on lung tissue are theoretically more likely to lead to unintended effects on the lung tissue if inadvertently inhaled 

As for other medicines, local and systemic absorption of mAb via inhalation of aerosolised formulations has been demonstrated in animal models. The likelihood of producing an aerosol with the required physical characteristics in the healthcare setting is low.   

Oral

Although mAb are generally believed to be denatured by enzymes and acid in the gut like any other protein, some evidence suggests that mAb can survive these gastric conditions and retain their biological activity.   

Nevertheless, in the occupational setting there is low potential for oral exposure to mAb because accidental hand-to-mouth contamination will be prevented by standard hand hygiene precautions.  

Toxicity

The toxicity of a substance must also be considered when making a risk assessment.  

mAb cannot be categorised into a single hazard category (unlike cytotoxic chemotherapy agents and radiopharmaceuticals); each molecule must be assessed individually.​ Molecule-specific information can be found in the SPC and Manufacturer’s Safety Data Sheet (MSDS) which will be available from the manufacturer.  

Potential toxicities include carcinogenicity, developmental toxicity (including teratogenicity), reproductive toxicity, and organ toxicity at very low doses.  

Worldwide organisations have established definitions for hazardous medicines and have formulated lists of such medicines based on these criteria, for example National Institute for Occupational Safety and Health (NIOSH) Hazardous Drug Exposures in Healthcare and the European Trade Union Institute (ETUI) list of hazardous medicinal products. 

At the time this article was published, there was only one unconjugated mAb on these lists.  

We discuss the potential toxicities in more detail within this section. Lack of evidence of harms in practice suggest that the occupational exposure risk will be low for most unconjugated mAb. 

Genotoxicity and mutagenicity

There is no regulatory requirement to test mAb for genotoxicity and mutagenicity during medicine licensing because of their molecular properties: 

  • the large molecular size prevents them from entering the cell nucleus and directly interacting with DNA 
  • the mechanism of action involves binding to antigens on cell surfaces and targeting specific proteins rather than disrupting DNA replication or repair processes 

This means little information about these toxicities is available and there is currently no evidence that mAb are genotoxic.    

Organ toxicity

The clinical toxicity profiles of the medicines are known for therapeutic doses. The risk of toxicity from occupational exposure to mAb remains uncertain, because of potential drug accumulation and the long half-life characteristic of mAb. Nevertheless, extrapolation from clinical toxicity is unlikely to be appropriate: much smaller quantities are involved and the likelihood of systemic absorption is low. ​  

Cytotoxicity

There is currently no evidence that mAb are cytotoxic. They exert their effects through mechanisms including antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxic activity. mAb cannot be classified as cytotoxic agents unless they are conjugated to a directly acting cytotoxic compound. ​  There is currently no evidence for increased risk of malignancy induced by handling of mAb.  

Developmental toxicity and teratogenicity

There is currently no evidence of developmental toxicity resulting from occupational exposure to mAb and this risk remains unknown. However, some mAb have been shown to be teratogenic or to cause other developmental toxicity when administered at therapeutic doses. 

Immunotoxicity

As with all protein-based therapeutics (for example, insulin), there is a theoretical risk of patients developing anti-drug antibodies at therapeutic dosing. This is dependent on many individual patient and treatment factors. There is limited evidence of staff developing detectable anti-drug antibodies after occupational exposure. There is a theoretical concern that exposure to a mAb could lead staff members to develop neutraliszing antibodies. Theoretically, these could, potentially affect their ability to receive therapeutic treatment with the same molecule in the future, however, there is currently no evidence to support this risk. ​  

The risk of immunogenicity should be assessed specifically for each molecule or biosimilar. This is challenging because immunogenicity assays are highly dependent on the sensitivity and specificity of the assay which may be influenced by factors including; methodology, sample handling, timing of sample collection, concomitant medicines, and underlying disease. This information is often available in the Summary of Product Characteristics. For the same reason any attempt at sub-classification of these molecules should be approached with caution. ​  

Further reading 

Alexander et al,. Australian consensus guidelines for the safe handling of monoclonal antibodies for cancer treatment by healthcare personnel. Internal Medicine Journal. October 2014. 

Clinical Oncology Society of Australia. Position Statement: 2022 update to the safe handling of monoclonal antibodies in healthcare settings. Asia Pacific Journal of Clinical Oncology, 10 March 2023. 

Halsen & Krämer. Assessing the risk to health care staff from long-term exposure to anticancer drugs – the case of monoclonal antibodies. Journal of Oncology Pharmacy Practice. July 2010.  

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