Antibody Drug Conjugates
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Antibody Drug Conjugates Christine S. Nervig1 and Shawn C. Owen1,2 1 Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA 2 Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA
Synonyms ADC; ADCs
Definition Antibody drug conjugates (ADCs) are hybrid therapeutics that combine the specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule drugs. ADCs are designed for targeted delivery of the cytotoxic payload directly to the desired site of action to increase efficacy and minimize off-target effects. ADCs consist of three essential components – the antibody, the drug, and the chemical linker connecting the two (Fig. 1). Accordingly, careful consideration is given to the design of each part. An optimal ADC has high target cell specificity, a long circulation half-life, minimal immunogenicity, and low off-target toxicity (McCombs and Owen 2015).
(a) Antibody: Monoclonal antibodies are the targeting agent in ADC therapies. The development of a successful antibody for an ADC therapy requires an antigen that is prevalent on the target cells and absent in normal tissue in order to allow for specific targeting to the tumor (Chau et al. 2019). It is important to note that serious ADC side effects can arise from antigen expression on unrelated cell types. For example, HER2 expression in heart tissue can lead to cardiotoxicity in trastuzumab-based ADCs (Kondapalli 2016). After antigen selection, antibodies are developed against the desired target. It is critical for the antibody to be able to induce receptormediated internalization for the ADC to be effective. The majority of antibodies in approved ADCs are of the IgG1 isotype, with IgG4 as the second isotype used (Mylotarg ® and Besponsa ®) (Khongorzul et al. 2020). Importantly, either of these isoforms impart long half-life, providing pharmacokinetic advantages to the ADC product compared to the free small-molecule drug. In order to minimize immunogenicity, these antibodies are humanized, with the exception of one chimeric ADC (Adcetris ®) that has been approved. Minimal antibody engineering is required since drug conjugation can occur with native amino acid residues (Khongorzul et al. 2020). (b) Payload: Several criteria must be met in choosing an appropriate payload for ADCs
© Springer Nature Switzerland AG 2020 S. Offermanns, W. Rosenthal (eds.), Encyclopedia of Molecular Pharmacology, https://doi.org/10.1007/978-3-030-21573-6_10064-1
2 Antibody Drug Conjugates, Fig. 1 Critical components of an ADC
Antibody Drug Conjugates
Antibody targets cancer cells
Linker attaches drug to antibody
Cytotoxic drug destroys cancer cells
including: solubility, amenability to conjugation, stability, and potency. The drug must be hydrophilic enough to allow for both conjugation to the antibody in aqueous conditions and stability of the resulting conjugate. Many potential drugs suffer from low solubility, which can be somewhat ameliorated by employing hydrophilic linkers. The payloads m
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