Setting occupational exposure limits for antibody-drug conjugates

Diplôme Master d'études avancées Setting occupational exposure limits for antibody-drug conjugates eng 2020-09-22 author Schmidt Brian 868253 director Vernez David Antibody-drug conjugates are emerging as a potential primary therapeutic oncology intervention. While only a few ADCs have been approved for use on the market, over 70 antibody-drug conjugates (ADCs) were at the clinical development stage by 2019, indicating the ever-increasing relevance of such antibody-based therapies and prompting one reviewer to declare: ‘The era of the antibody is upon us'. Given the continuing advances in molecular, biological and clinical understanding it would not be far fetched to envision a future where ADCs are an ever more important subset of approved oncology therapies.10,26 The notion of attaching toxic molecules to tumor specific antibodies had been spoken of by Paul Erhlich as far back as the early 1900s, although scientific understanding of biology, biochemistry, tumors and the technology required was lacking. The first ADC was approved for market by the FDA in the year 2000 and only four others have been approved since. Recent market approvals tell a story of decades of advances in areas like conjugation chemistry which have allowed those initial dreams to become reality. 1,2,26 The current generation of ADCs rely on genotoxic or antimitotic payloads. These toxins interact directly with DNA or microtubule structures to kill cells or disrupt cell division. Unsurprisingly such molecules are often extremely potent and not well tolerated when used as free agents. Antibody-drug conjugates are a hybrid consisting of a biological antibody scaffold modified by chemical toxic payloads and joined by a linker. The concept is that the antibody allows for delivery of the toxin to specific cells based on antigen binding for that cell type, followed by internalization and resulting in antimitotic effects or cell death. This minimizes systemic exposure to the toxin and associated off-target effects.2,3 When ADCs and their manufacture are viewed from worker health protection perspective, the ADC and its components should be considered as biochemical hazardous substances. Society is willing to accept significant risks and well documented side effects when administering potent compounds to cancer patients in a bid to improve prognosis. Here context is everything, as the same risks cannot be accepted for otherwise healthy workers. Whilst laws and regulations aimed at protecting worker health are in place around the globe, the challenge presented by pharmaceutical active ingredients are over and above those of ‘regular' hazardous substances. Many large private business organizations are required to develop in-house occupational exposure limits, driven by a need to ensure the safety of their workforce. This is particularly notable in the pharmaceutical industry for which few nationally set OELs are available. Setting occupational exposure limits for ADC's may present unique challenges which are explored in this manuscript. 24,25,31,32,43 Through a process of literature review and practical OEL setting for one ADC (brentuximab vedotin), it is concluded that existing OEL setting methodologies may be applied to ADCs which enable occupational hygienists to assess and manage workplace exposure risk. ADC toxicity is driven in the main by the toxic payload molecule, which is perhaps unsurprising, given that payload candidates are often orders of magnitude more potent than even traditional chemotherapy drugs. Still, ADCs are complex molecules which fundamentally change the pharmacokinetic and pharmacodynamic characteristics of the payloads they deliver, including the potential for significant off-target toxicity and unexpected increases in internal exposure. OEL setting therefore requires careful consideration of the specificities of ADCs in general, the characteristics of the particular molecule being assessed, and the role different elements of the ADC molecule play in causing unacceptable toxicities. Dewey 610 Dewey 615 Master of Advanced Studies in Toxicology 31 Section des sciences pharmaceutiques 17 3 Faculté de médecine 2 false af5f336a-d02b-488d-b683-5ef1f529bdff Master thesis Restricted Brian Schmidt MASTox FINAL Thesis A.pdf 785292 application/pdf restrictedAccess Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine

Title	Published in	Access level	OA Policy	Year	Views	Downloads

Setting occupational exposure limits for antibody-drug conjugates				2020	58	3

Archive ouverte UNIGE

Schmidt, Brian