Evaluation du risque pour la fabrication des anticorps monoclonaux

9 octobre 2010

S. Langford Huddersfield Royal Infirmery, Huddersfield, UK

Monoclonal antibodies (MABs) were introduced into clinical practice in 1986. Since then their use has be come established in the treatment of a variety of disease states including cancer, rheumatoid arthritis, transplanted organ rejection, psoriasis and allergic asthma. Monoclonal antibodies have profound activity at the cellular level, hence concerns were raised involving the handling of these agents, given the well established occupational exposure risks in handling small molecule cytotoxic agents. This has been exacerbated by a lack of accessible information and guidance for healthcare staff.

In 2008 a team of pharmacists and nurses at the University Hospital of North Staffordshire published a paper setting out a proposed risk assessment tool. Subsequent correspondence and published sources has added to the information available and is reviewed in this presentation.

The risks : From experience with traditional cytotoxic agents, the risks to healthcare staff arise from the inhalation of the aerosols formed in the preparation and administration of MABs and also chronic low grade exposure to multiple agents.

  1. MABs are proteins containing variable amounts of murine protein content to fully human forms and all forms have the potential to cause immunogenic responses.
  2. In the absence of occupational health studies, toxic risks are extrapolated from the side effects of therapeutic doses. While some of the toxic effects of MABs are related to effects on the disease state e.g. tumour lysis syndrome ; toxicities also arise from their intrinsic activity.
  3. Intrinsic activities include the direct activation of T cells, boosting the immune response and binding to tissue antigens. MABs can be profoundly immunosuppressant e.g. Rituximab can cause the complete depletion of circulating B cells within 2 weeks.
  4. Alemtuzumab targeting CD52, which is widely distributed, triggers complement dependent cytotoxicity and severe prolonged lymphopenia.
  5. Cetuximab and Panitumumab acting as anti EGFR agents affect skin integrity and may cause severe skin reactions.

To summarise the risks from MABs include cytotoxic and profound immuno-suppressive properties. The latter may give rise to opportunistic infections and a low risk of the development of malignancy. All MABs may give rise to antibodies and low dose episodic dosing is more immunogenic that single high doses. While targeted at specific antigens, these may be expressed in several tissues. Finally humanised antibodies may have a long half life of days to weeks.

Mitigating factors :

  1. Monoclonal antibodies are high molecular weight materials, typically 150KDa and will not breach the skin.
  2. If ingested MABs are rapidly broken down by gut enzymes and acids.
  3. Immunogenicity for humanised MABS is not of the classical type, forming binding, not neutralising antibodies and do not have “memory”.
  4. Toxicity is mediated at the cellular level and does not involve intracellular damage to genetic material.
  5. There has little evidence to date of occupational ill health arising from the use of MABs.

On the balance of risk simple precautions taken during the preparation and administration of MABs, such as wearing gloves, hand-washing and face masks, backed up with robust surface cleaning of handling areas are likely to further reduce potential risks.

Currently we simply do not know all the risks of chronic low grade exposure to the multiplicity of monoclonal antibodies used in clinical practice.

Diapos-Assessing the risk of handling Monoclonal Antibodies Diapos-Assessing the risk of handling Monoclonal Antibodies

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