Chapter 9: Immunotoxicity Testing for Drug–Nanoparticle Conjugates: Regulatory Considerations

Nanoscale materials are being developed for use in a wide variety of products including pharmaceuticals that are regulated by the U.S. Food and Drug Administration (FDA). Some of these represent reformulations of existing drugs or slow release degradable systems. A different category are drugs conjugated to durable nanoparticles (NPs), which do not degrade in the body. In all cases, these novel materials are subject to the same rules and regulations concerning drug development that apply to small molecules and therapeutic proteins. All drugs, including NP–drug conjugates, should be evaluated for immunotoxicity during development. This evaluation is governed by the ICH S8 guidance for small molecule drugs or by the ICH S6 guidance for protein drugs. These guidances continue to apply for drugs conjugated to NPs. Under S8, the primary level of evaluation is a weight of evidence review of the data collected in standard toxicology studies. If data suggestive of immunotoxicity are found, further focused studies may be needed. For proteins, the primary issue is drug hypersensitivity and samples should be collected from non-clinical studies to fully evaluate the role of any anti-drug antibodies. Several studies from CDER/ FDA laboratories are used to illustrate how the principles described in the guidance documents could be applied in a real-world situation.