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Research ADCs

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A brief history of ADCs

ADCs have the potential to be a new approach to the targeted and selective treatment of cancer1

Critical parameters for development of an ADC

Critical parameters for development of an ADC

The first step toward successful development of an ADC is a comprehensive understanding of the cancer biology, the identification of the proper target antigen for the tumor type, and a careful choice of the 3 components of the ADC2,3

Looking back at first-generation ADCs

The development of an ADC is a design-driven and continual process2

The design of first-generation ADCs was aimed at enhancing the selectivity of traditional chemotherapeutic agents, such as methotrexate, the Vinca alkaloids, and doxorubicin, by linking them to monoclonal antibodies.4

Early ADC researchers realized the importance of 3 critical factors for the therapeutic success of the ADC4:

  • The nature of the chemical linker connecting the cytotoxic to the
    monoclonal antibody
  • The ability of the ADC to be internalized into the target cell
  • The intracellular release mechanism that would cleave the linker to release the active cytotoxic

The challenges of first-generation ADCs

Early ADCs had limitations for a variety of reasons

  • Linker instability: Early linkers were either too stable, resulting in low potency and reduced efficacy, or too unstable, resulting in poor targeting and high systemic toxicity4,5
  • Cytotoxics without sufficient potency: Circulating serum concentrations of the ADC were not in the necessary therapeutic range4,5
  • Inefficient internalization: Not all antibodies were efficiently internalized, and the number of ADC molecules delivered to the target tumors was low4
  • Limited expression of the target antigen: Failure to choose an appropriate target antigen that was sufficiently overexpressed on the target cell surface led to low concentrations of the ADC inside the tumor cell4
  • Immunogenicity of monoclonal antibodies: Early conjugates employed murine or murine/chimeric (partly human) monoclonal antibodies that resulted in an immune response and the generation of human antimurine antibodies (HAMA), preventing further treatment4,5

The potential of second-generation ADCs

Building on insights from early research has led to the development of a new generation of ADCs2

Second-generation ADCs are designed to deliver potent anticancer agents to tumors in a targeted manner to limit systemic exposure.3,6-9 Research has confirmed that the success of targeted ADCs depends on 3 components1:

  1. Antibody selection
  2. Potency of the cytotoxic
  3. Method of linkage of the antibody to the cytotoxic

The critical role of the linker

  • The therapeutic success of an ADC is dependent upon the linker component1,4
  • Linker technology impacts ADC potency, specificity, and safety1,4
  • Early ADC linkers were derived from cleavable acid- and peptidase-labile hydrazones designed to cleave inside target tumor cells, but they cleaved at nontarget sites instead, which increased systemic toxicity1,4
  • Next, disulfide linkers were developed, which achieved greater in vivo stability but were recently found to be inefficient1,10

Optimizing the linker

To limit the systemic exposure of the ADC cytotoxics, noncleavable linkers, including thioether linkers, were recently developed.1,4

  • Noncleavable linkers are the most stable linkers currently used in the development of ADCs1
References:
1.
Ducry L, Stump B. Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21:5-13.
2.
Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169.
3.
Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054.
4.
Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107.
5.
Alley SC, Zhang X, Okeley NM, et al. The pharmacologic basis for antibody-auristatin conjugate activity. J Pharmacol Exp Ther. 2009;330:932-938.
6.
Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137-1146.
7.
Ricart AD, Tolcher AW. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245-255.
8.
Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925-932.
9.
Ghose T, Blair AH. Antibody-linked cytotoxic agents in the treatment of cancer: current status and future prospects. J Natl Cancer Inst. 1978;61:657-676.
10.
Austin CD, Wen X, Gazzard L, Nelson C, Scheller RH, Scales SJ. Oxidizing potential of endosomes and lysosomes limits intracellular cleavage of disulfide-based antibody-drug conjugates. Proc Natl Acad Sci U S A. 2005;102:17987-17992.