Chemoimmunoconjugate

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A chemoimmunoconjugate , also called antibody-drug conjugate , engl. Chemoimmunoconjugate , is an immunoconjugate that consists of a cell-binding component and a cytostatic agent . Chemoimmunoconjugates are potential drugs that are to be used primarily in oncology for the treatment of cancer diseases as part of cancer immunotherapy .

construction

Chemoimmunoconjugates consist of two main components. One component is a carrier molecule that binds to cancer cells as selectively as possible. In most cases this is a monoclonal antibody or a fragment of a monoclonal antibody or a corresponding antibody mimic . The carrier molecule serves on the one hand as a ligand for binding to the target structure ( target ) on the cell membrane of a cancer cell. The target structures are essentially tumor antigens or tumor-specific receptors, i.e. proteins or glycoproteins which , ideally , are only presented ( expressed ) by cancer cells on their cell surface . The other function of the carrier molecule is to bind a cytostatic - the second main component of a chemoimmunoconjugate.

function

The cytostatics used in conventional chemotherapy are not tumor-specific. Their mechanism of action is essentially based on the fact that strongly proliferating cells - mainly cancer cells - are significantly more sensitive to cytotoxic substances than most other body cells. Healthy body cells, which also divide quickly, are more and more destroyed with increasing dose, which limits the dose of the chemotherapeutic agent. On the other hand, the highest possible dose would be desirable in order to completely destroy all cancer cells. As a consequence of this narrow therapeutic range , suboptimal doses of chemotherapeutic agents are often administered. As a solution to this dilemma , tests with antibodies to which chemotherapeutic agents were covalently bound were carried out as early as the 1980s . If the antibody provides sufficient selectivity for cancer cells, the cytostatic agent can be enriched in the tumor or in individual cancer cells. The healthy tissue is therefore exposed to significantly lower amounts of active ingredient. The total dose of active ingredient can also be increased significantly in this way, if necessary.

Schematic representation of the endocytosis of an immunotoxin in a cancer cell.

The cancer cells internalize the bound antibodies by means of receptor-mediated endocytosis . The antibody-cytostatic conjugate is broken down in the lysosome and the active ingredient is released. This can then, for example, permanently damage the DNA of the cancer cell. The effects of multiple drug resistance that can otherwise be observed with the systemic administration of active substances , in which transporters such as P-glycoprotein (PGP), for example, channel the active substances out of the cell, are significantly reduced with the antibody-mediated administration.

When binding the active substance to the antibody, it is important that the chemical bond is as stable as possible both when the active substance is stored - usually in a buffered aqueous solution - and in the serum so that the active substance is not systemically released immediately after the injection. The release should ideally only take place inside the cell or, if necessary, in the immediate vicinity of the cancer cells. Essentially, peptide sequences , hydrazones and disulfides are used as so-called linkers between antibody and active ingredient . The peptide sequences used are structures which can be easily cleaved by lysosomal or endosomal enzymes ( proteases ). The hydrazones are acid-labile and are opened by low pH values ​​(<5.0). The disulfides are released through disulfide exchange, for example by glutathione , which is particularly present in high concentrations in cancer cells. The glutathione concentration in malignant cells is over a thousand times higher than in plasma. In this way, various cytostatics, for example from the families of the vinca alkaloids , the folic acid antagonists or the anthracyclines , can be bound to monoclonal antibodies and released in tumor cells.

In order to increase the potency of the conjugate, more than one effector molecule is usually bound to the antibody. In most cases, the binding to the antibody is not targeted, which increases the likelihood that one of the effector molecules will bind in the area of ​​the paratopsis of the antibody and thereby lose the ability of the antibody to bind to an epitope . The number of effector molecules is therefore usually limited to less than ten units. One approach to this problem is the conjugation of branched or dendrimeric effector oligomers on the antibody. This principle is also used , for example, in radioimmunoconjugates .

Examples

A number of chemoimmunoconjugates are in clinical testing. In many cases, highly potent cytostatics, such as doxorubicin , are bound to monoclonal antibodies, which have considerable side effects when administered systemically. In the example of doxorubicin, this is the cardiotoxicity of this compound. Other cytostatics conjugated to antibodies in addition to the vinca alkaloids, antifolates and anthracyclines already mentioned, for example the maytansinoids . Also, α-amanitin , the main poison of Amanita mushrooms , is conjugated as a cytostatic agent to antibodies.

Instead of antibodies, antibody mimetics such as aptamers can also be used.

Demarcation

In the chemo-immunotherapy a chemotherapeutic agent (e.g., such as 5-fluorouracil ) in a treatment cycle together with an immunotherapeutic agent (e.g., interleukin-2 administered) to the patient. The chemotherapeutic agent is administered systemically in a conventional manner. In addition, the patient receives an immunotherapeutic agent to kill off as many cancer cells as possible.

Immunotoxins are very similar in structure to chemoimmunoconjugates, but instead of the cytostatic agent they have a toxin as an effector.

literature

  • RV Chari: Targeted cancer therapy: conferring specificity to cytotoxic drugs. In: Acc Chem Res 41, 2008, pp. 98-107. PMID 17705444 (Review)

Individual evidence

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  11. ↑ DA Johnson and BC Laguzza: Antitumor xenograft activity with a conjugate of a Vinca derivative and the squamous carcinoma-reactive monoclonal antibody PF1 / D. In: Cancer Research 47, 1987, pp. 3118-3122. PMID 3495327
  12. ↑ WC Shen et al: Targeting, internalization, and cytotoxicity of methotrexate-monoclonal anti-stage-specific embryonic antigen-1 antibody conjugates in cultured F-9 teratocarcinoma cells. In: Cancer Research 46, 1986, pp. 3912-3916. PMID 2873883
  13. ^ RO Dillman et al.: Superiority of an acid-labile daunorubicin monoclonal antibody immunoconjugate compared to free drug. In: Cancer Research 48, 1988, pp. 6097-6102. PMID 3262420
  14. ↑ C. Wängler et al: Antibody-dendrimer conjugates: the number, not the size of the dendrimers, determines the immunoreactivity. In: Bioconjug Chem 19, 2008, pp. 813-820. PMID 1836151
  15. ^ C. Wängler et al: Improved syntheses and applicability of different DOTA building blocks for multiply derivatized scaffolds. In: Bioorganic & Medicinal Chemistry 16, 2008, pp. 2606-2616. PMID 18065226
  16. ↑ LD Apelgren et al .: Chemoimmunoconjugate development for ovarian carcinoma therapy: preclinical studies with vinca alkaloid-monoclonal antibody constructs. In: Bioconjug Chem 4, 1993, pp 121-126. PMID 7873643
  17. ↑ HK Erikson: Antibody-Maytansinoid Conjugates Are Activated in Targeted Cancer Cells by Lysosomal Degradation and Linker-Dependent Intracellular Processing. In: Cancer Res 66, 2006, pp. 4426-4433. PMID 16618769
  18. ↑ AW Tolcher et al: Cantuzumab Mertansine, a Maytansinoid Immunoconjugate Directed to the CanAg Antigen: A Phase I, Pharmacokinetic, and Biologic Correlative Study. In: Journal of Clinical Oncology 21, 2003, pp. 211-222. PMID 12525512
  19. ↑ Stephen Parmley: Resurrecting a Magic Bullet. In: Science-Business eXchange. 7, 2014, doi : 10.1038 / scibx.2014.1397 .
  20. ↑ YF Huang et al: Molecular assembly of an aptamer-drug conjugate for targeted drug delivery to tumor cells. In: ChemBioChem 10, 2009, pp. 862-868. PMID 19253922