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Cytotoxic agent

Cytotoxic agents incorporated into ADCs may be up to 1000-fold more potent than currently used chemotherapies1

Cytotoxic agents are drugs used in the treatment of cancer. Because of their targeted nature, ADCs are designed to allow for the use of highly potent, normally intolerable, anticancer cytotoxics.2,3

Cytotoxic agent

  • Preclinical studies suggest that criteria for the ideal cytotoxic should include1,3-5
    • High in vitro potency
    • Sensitivity of the cancer type to the class of the cytotoxic (eg, antitubulin agents are frequently used in breast cancer)
    • Ability to induce cell death
  • The cytotoxic also should be chemically tractable and stable while bound to the monoclonal antibody4,6
  • It is important that the therapeutically appropriate amount of the cytotoxic be linked to the monoclonal antibody to optimize the potential effectiveness of the ADC once it reaches the target cancer cell1
  • Different ADCs have different characteristics, so it is important to evaluate the optimal monoclonal antibody-linker-cytotoxic combination for each cancer type and target antigen under investigation7,8
  • Cytotoxics in development in ADCs include maytansinoids, auristatins, calicheamicins,
    CC-1065, duocarmycins, anthracyclines, and doxorubicin derivatives4-6,10-13

Components of ADCs currently under investigation: cytotoxic agents

Name* Target Mode of action
Doxorubicin derivatives9 Topoisomerase II
DNA complexes		 Inhibit DNA religation, leading to DNA double-strand breaks
Maytansinoids3 α-Tubulin Prevent tubulin polymerization
Auristatins3 α-Tubulin Prevent tubulin polymerization
Calicheamicins3 Sequence-specific minor groove of DNA Cause double-strand DNA breaks
CC-10651 Sequence-specific minor groove of DNA Induces adenine alkylation
Duocarmycins10,11 Bind to specific minor groove of DNA Break down adenine-specific molecules in the DNA structure
Anthracyclines12,13 DNA, RNA complexes Inhibit DNA and RNA synthesis by intercalating between base pairs, preventing replications
*This is not a complete list of cytotoxics under investigation in ADCs.
References:
1.
Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107.
2.
Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054.
3.
Ricart AD, Tolcher AW. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245-255.
4.
Hamann PR. Monoclonal antibody-drug conjugates. Expert Opin Ther Pat. 2005;15:1087-1103.
5.
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.
6.
Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169.
7.
Erickson HK, Park PU, Widdison WC, et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 2006;66:4426-4433.
8.
Kovtun YV, Goldmacher VS. Cell killing by antibody-drug conjugates. Cancer Lett. 2007;255:232-240.
9.
Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56:185-229.
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.
11.
Boger DL. Design, synthesis, and evaluation of DNA minor groove binding agents: the duocarmycins. Pure Appl Chem. 1994;66:837-844.
12.
Beck A, Senter P, Chari R. World Antibody Drug Conjugate Summit Europe: February 21-23, 2011; Frankfurt, Germany. MAbs. 2011;3:331-337.
13.
Chemoth.com website. Anthracyclines. http://chemoth.com/types/anthracyclines. Accessed October 31, 2011.