What is Calicheamicin?

What is Calicheamicin?

Calicheamicin is a class of enediyne anti-tumor antibiotics derived from the bacteria of Micromonas Escherichia. It is extremely toxic to all cells, and the most famous of which is Calichemicin γ1. It was first separated from the chalky soil or "calichi pit" in Kerrville, Texas in the mid-1980s. In 2000, the immunoconjugate N-acetyl dimethyl hydrazide Calicheamicin was developed to target CD33 antigen and used as a targeted therapy for acute myeloid leukemia (AML) in non-solid tumor cancer.

Figure 1: A. Calicheamicin; B. N-acetyl-calicheamicin.

Mechanism of action

The researchers pointed out that this new compound called Calicheamicin can target DNA and cause strand breaks. Studies showed that Calicheamicin binds to the DNA in the minor groove, and then they undergo a reaction similar to Bergman's cyclization to generate diradical substances. Then, this double-radical 1,4-didehydrobenzene abstracts hydrogen atoms from the deoxyribose (sugar) backbone of DNA, which eventually leads to strand breaks.

The damaging effect of calicheamicin on DNA can lead to cell apoptosis and cell death at very low concentrations. In animal models, anti-tumor effect of calicheamicin was observed at doses of 0.5–1.5 μg/kg. Compared with doxorubicin, its potency was increased by 4000 times. Unfortunately, the use of Calicheamicin alone showed a very narrow therapeutic window and delayed toxicity, thus hindering its development.

Calicheamicins-based ADCs

Although Calicheamicin cannot be developed as an independent drug, when combined with antibodies, it can deliver very effective cytotoxic drugs specifically targeting tumor cells, which can reduce collateral damage to normal tissues.

Gemtuzumab ozogamicin (Mylotarg®)

On May 17, 2000, the FDA approved gemtuzumab ozogamicin which is the first monoclonal antibody-drug conjugate (ADC) linking calicheamicin to a monoclonal antibody. The drug consists of N-acetyl-γ-Calicheamicin bound to a humanized anti-CD33 IgG4κ antibody (hP67.6) via a bifunctional linker (the DAR of each mAb contains 2-3 calicheamicin).

Gemtuzumab ozogamicin binds to CD33-positive cells, and then decompose in the lysosomal vesicles with the acidic pH and then release the cytotoxic calicheamicin through the reductive cleavage of the disulfide bond, causing DNA double-strand breaks, and eventually leading to cell death.

Figure 2: Schematic representation of Calicheamicins-based ADCs. A: Gemtuzumab ozogamicin; B. Inotuzumab ozogamicin. (derived from Kumar, A., 2017)

Inotuzumab ozogamicin

Inotuzumab ozogamicin, also known as CMC-544, is an antibody-drug conjugate, approved by the FDA in August 2017, is targeted at CD22 antigen present on B cells. N-acetyl ɣ-Calicheamicin 1, 2-dimethyl hydrazine dichloride (NAc ɣ-calicheamicin DMH) is conjugated with the humanized monoclonal IgG4 antibody G544 via an acid-labile 4-(4'-acetylphenoxy) butyric acid linker. Once binding to the CD22 receptor on the B cell surface, inotuzumab ozogamicin will be endocytosed and fused with lysosomes. In an acidic environment, the acidic linker degrades to release calicheamicin, and the kinase causes cell death.

As an antibody-drug conjugate (ADC), inotuzumab ozogamicin preferentially delivers cytotoxic agents (calicheamicin) to tumor cells, minimizing the replacement of normal tissues, thereby increasing the therapeutic index.

With our comprehensive ADC cytotoxin synthesis platform, BOC Sciences is ready to provide you with high-quality calicheamicin and its derivatives. Our tailor-made services and high-quality products will make a huge contribution to the success of your project.

References:

  1. Maiese, William M, et al. Calicheamicins, a novel family of antitumor antibiotics: taxonomy, fermentation and biological properties. Journal of Antibiotics. 1989; 42(2):558-563.
  2. Lee, May D, et al. Calichemicins, a novel family of antitumor antibiotics. 3. Isolation, purification and characterization of calichemicins β1Br, γ1Br, α2I, α3I, β1I, γ1I, and Δ1I. Journal of Antibiotics. 1989; 42(7):1070-1087.
  3. S. Walker, et al. Cleavage behavior of calicheamicin gamma 1 and calicheamicin T. Proc Natl Acad Sci USA. 1992; 89 (10):4608-2.
  4. Kumar, A., White, J., James Christie, R., Dimasi, N., & Gao, C. Antibody-Drug Conjugates. Platform Technologies in Drug Discovery and Validation. 2017:441-80.
  5. HURYN, D. M., & WIPF, P. Natural product chemistry and anticancer drug discovery. Cancer Drug Design and Discovery. 2008;107-30.
  6. Dosio F., Brusa P, Cattel L Immunotoxins and Anticancer Drug Conjugate Assemblies: The Role of the Linkage between Components. Toxins. 2011; 3(7):848-883.
* Only for research. Not suitable for any diagnostic or therapeutic use.
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