Recent developments in combination therapy, antibody-drug conjugation, and related advanced concepts like pHLIP® Drug Conjugates (PDCs) are based on linking together two compounds with different functionalities. Historically, linker moieties used to represent simple conjugation elements, but have since developed into crucial parts of all the various kinds of drug conjugates nowadays on the market. Chain length and physicochemical properties, as well as triggered traceless release properties have become important parameters for linker molecules that significantly influence the pharmacological characteristics and efficacy of the main actors in the drug assembly. The ever-growing sophistication and variation in linker design have given rise to a new and distinct field of knowledge in synthetic chemistry termed Linkerology. Keeping step with the latest advances in this field, Iris Biotech has developed a panoply of over 100 specialized and cutting-edge linker constructs, adding to our existing portfolio of some 1000 conventional aliphatic and PEG-based linkers.

A great number of natural and synthetic compounds display promising modes of action, but suffer from deleterious side effects due to a lack in specificity. Typical examples are toxins such as amanitin or MMAE, or psychopharmaceutics like benzodiazepines. The attachment of a targeting moiety to an API via a linker molecule may help curing any lack of specificity and may turn an otherwise toxic compound into a patient-friendly drug.

Making use of this approach, immunosuppressants such as glucocorticoids may gain efficacy by being delivered to a specific target, thus becoming available at the very location they are needed without affecting other parts of the organism. Natural products with promising anti-tumor properties such as Herboxidiene and Roridin E are being promoted to interesting drug candidates by means of specific delivery and traceless release technologies.

Another field that utilized sophisticated linker design is the targeted protein degradation via proteolysis-targeting chimeras (PROTACs^®). This technology is emerging as a novel therapeutic method to address diseases caused by the irregular expression of certain proteins. By conjugating a small molecule able to recruit a specific E3 ubiquitin ligase to a tailored protein-targeting moiety, this degradation technique opens the door to a vast filed of potential targets in the proteome.

Various types of linker designs.

       *** Coming Soon ***

➔ Follow this link to explore the new Linkerology section on our webpage!
➔ Do you require a custom-made linker? Contact our Custom Synthesis service!
➔ If you require an in-depth introduction to this new product category, our scientific team members would be pleased to schedule an online presentation with you. Contact us via our website.

References:

• Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy; U. B. Hagemann, K. Wickstroem, S. Hammer, R. M. Bjerke, S. Zitzmann-Kolbe, O. B. Ryan, J. Karlsson, A. Scholz, H. Hennekes, D. Mumberg and A. S. Cuthbertson; Cancer Biother Radiopharm 2020; 0: null. https://doi.org/10.1089/cbr.2020.3568
• Trimethyl Lock: A Multifunctional Molecular Tool for Drug Delivery, Cellular Imaging, and Stimuli-Responsive Materials; O. A. Okoh and P. Klahn; Chembiochem : a European journal of chemical biology 2018; 19: 1668-1694. https://doi.org/10.1002/cbic.201800269
• Invention of stimulus-responsive peptide-bond-cleaving residue (Spr) and its application to chemical biology tools; A. Shigenaga, J. Yamamoto, T. Kohiki, T. Inokuma and A. Otaka; J Pept Sci 2017; 23: 505-513. https://doi.org/10.1002/psc.2961
• Modulating Therapeutic Activity and Toxicity of Pyrrolobenzodiazepine Antibody-Drug Conjugates with Self-Immolative Disulfide Linkers; T. H. Pillow, M. Schutten, S. F. Yu, R. Ohri, J. Sadowsky, K. A. Poon, W. Solis, F. Zhong, G. Del Rosario, M. A. T. Go, J. Lau, S. Yee, J. He, L. Liu, C. Ng, K. Xu, D. D. Leipold, A. V. Kamath, D. Zhang, L. Masterson, S. J. Gregson, P. W. Howard, F. Fang, J. Chen, J. Gunzner-Toste, K. K. Kozak, S. Spencer, P. Polakis, A. G. Polson, J. A. Flygare and J. R. Junutula; Molecular cancer therapeutics 2017; 16: 871-878. https://doi.org/10.1158/1535-7163.MCT-16-0641
• Syntheses and kinetic studies of cyclisation-based self-immolative spacers; S. Huvelle, A. Alouane, T. Le Saux, L. Jullien and F. Schmidt; Org Biomol Chem 2017; 15: 3435-3443. https://doi.org/10.1039/c7ob00121e
• Design and Synthesis of Tesirine, a Clinical Antibody-Drug Conjugate Pyrrolobenzodiazepine Dimer Payload; A. C. Tiberghien, J. N. Levy, L. A. Masterson, N. V. Patel, L. R. Adams, S. Corbett, D. G. Williams, J. A. Hartley and P. W. Howard; ACS Med Chem Lett 2016; 7: 983-987. https://doi.org/10.1021/acsmedchemlett.6b00062
• Mechanisms of drug release in nanotherapeutic delivery systems; P. T. Wong and S. K. Choi; Chem Rev 2015; 115: 3388-432. https://doi.org/10.1021/cr5004634
• Self-immolative spacers: kinetic aspects, structure-property relationships, and applications; A. Alouane, R. Labruere, T. Le Saux, F. Schmidt and L. Jullien; Angew Chem Int Ed Engl 2015; 54: 7492-509. https://doi.org/10.1002/anie.201500088
• Linker Technologies for Antibody–Drug Conjugates; B. Nolting; Antibody-Drug Conjugates L. Ducry 2013; 1045: 71-100. https://doi.org/10.1007/978-1-62703-541-5_5
• Cleavable linkers in chemical biology; G. Leriche, L. Chisholm and A. Wagner; Bioorg Med Chem 2012; 20: 571-82. https://doi.org/10.1016/j.bmc.2011.07.048
• Dendritic chain reaction: responsive release of hydrogen peroxide upon generation and enzymatic oxidation of methanol; M. Avital-Shmilovici and D. Shabat; Bioorg Med Chem 2010; 18: 3643-7. https://doi.org/10.1016/j.bmc.2010.02.038

• “PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.