Regulatory Forum Opinion Piece *: Differences between Protein-based Biologic Products (Biotherapeutics) and Chemical Entities (Small Molecules) of Relevance to the Toxicologic Pathologist
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With the advances in cell culture methodologies and molecular biology that have occurred over the past several decades, biologics have become as common as small molecules within the portfolios of the pharmaceutical industry. Toxicologic pathologists should be aware of some of the fundamental differences between small molecules and biologics. Effects are not always observed in studies following administration of biologics. When findings are observed, the toxicologic pathologist should initially determine whether the effect(s) are mediated (directly or indirectly) via the intended pharmacology, exaggerated pharmacology, an immune response, and/or off target effects. Following this determination, the toxicologic pathologist should provide an assessment regarding the relevance of the findings to the intended clinical population, usually humans. The toxicologic pathologist may also be asked to assess unusual species and models. Given their broad background in physiology and immunology, toxicologic pathologists are uniquely positioned to provide this input to drug development teams.
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The difference between small molecules and biologics likely reflects modality-specific mechanisms, where biologics more frequently trigger immune-driven responses compared to small molecules.
“This difference likely reflects modality-specific mechanisms, where biologics more frequently trigger immune-driven responses compared to small molecules (Leach, 2013; Shah et al., 2020).”
From A large-scale concordance study of toxicity findings across preclinical species and humans for small molecules and biologics (2026) · cites this paper as Leach, 2013
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- Authors
- Leach, M. W.
- Affiliations
- Pfizer (United States) (US)
- Corresponding author
- Leach, Michael W.
- ORCID
- Leach, Michael W.
- Venue
- Toxicologic Pathology
- Publisher
- SAGE Publications
- Published
- 2012-06-28
- Volume
- 41
- Issue
- 1
- Pages
- 128-136
- ISSN
- 0192-6233 (ISSN-L)
- 1533-1601
- OpenAlex
- W2111420636
- Cited by
- 22
- References
- 19
- Citations by year
- 2026: 3 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 2 · 2018: 1 · 2017: 4 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 1
- FWCI
- 0.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Toxicologic Pathology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Keywords
- biologics, small molecules, immune response, off-target effects, animal-to-human extrapolation, drug development
- MeSH terms
- Animals, Biological Assay, Biotechnology, Dose-Response Relationship, Drug, Humans, Toxicology, Biomedical Research, Drug Discovery, Biosimilar Pharmaceuticals
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