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Research ADCs

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Stable linker

Stable linkers are designed to allow ADCs to remain inactive while in circulation1-4

Linkers are designed to prevent the release of the cytotoxic into circulation.1,2,4,5 Linker stability in circulation is critical, because it controls the distribution and delivery of the cytotoxic to the target cell.4 Preclinical studies suggest that the selection of a linker should depend on the tumor type, the cytotoxic selected, linker stability in circulation, and the ability of the linker to be cleaved within target cells.4

Linker

  • Linkers can be used to exploit intracellular conditions for drug release in the target cell6
  • After the monoclonal antibody binds onto the target antigen, the ADC/antigen complex is internalized via endocytosis. Once internalized in the target cell, the linker should be readily cleavable1,2
  • Selection of the appropriate linker influences cellular cytotoxicity, because intracellular cleavage of the linker allows efficient release of the cytotoxic inside the cancer cell1
  • The half-lives of cytotoxic retention (stability) vary among different types of linkers6
  • The use of more stable linkers may allow delivery of the cytotoxic to the cancer cell over an extended period of time compared with more unstable linkers that may have shorter half-lives7
  • Modification of linker technology may influence the potency and anticancer effectiveness of the ADC6
  • Certain characteristics of ADCs may differ between cancers; therefore, it is important to individually evaluate optimal drug-linker combinations for each cancer type and target antigen2,8
  • Current linkers in development include hydrazone, disulfide, thioether, peptide, hydrophilic, and DNA alkylator6

Components of ADCs currently under investigation: linker

Linker* Release mechanism
Hydrazone Designed for serum stability and degradation in acidic compartments within the cytoplasm6
Peptide Designed to be enzymatically hydrolyzed by lysosomal proteases such as cathepsin B4,6
Disulfide Designed to be cleaved through disulfide exchange with an intracellular thiol, such as glutathione2,6
Thioether Nonreducible and designed for intracellular proteolytic degradation3,6
Hydrophilic Designed to improve activity against multidrug resistant cells and carry a higher maytansinoid load9
DNA alkylator Designed for DNA-specific binding that increases reactivity, deactivates the cytotoxic, and reactivates only after the cytotoxic is cleaved9,10
*This is not a complete list of linkers under investigation in ADCs.
References:
1.
Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054.
2.
Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107.
3.
Oflazoglu E, Stone IJ, Gordon K, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171-6180.
4.
Sanderson RJ, Hering MA, James SF, et al. In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843-852.
5.
Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137-1146.
6.
Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169.
7.
Alley SC, Zhang X, Okeley NM, et al. The pharmacologic basis for antibody-auristatin conjugate activity. J Pharmacol Exp Ther. 2009;330:932-938.
8.
Ducry L, Stump B. Antibody–drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21:5-13.
9.
Beck A, Senter P, Chari R. World Antibody Drug Conjugate Summit Europe: February 21-23, 2011; Frankfurt, Germany. MAbs. 2011;3:331-337.
10.
de Groot V. Novel ADC linker-drug technology for next generation ADC products. Presented at: Cambridge Healthtech Institute 10th Annual PepTalk: the Protein Science Week; January 10-14, 2011; San Diego, CA. Syntarga website: download January 14, 2011. http://www.syntarga.com. Accessed October 24, 2011.