Immunoconjugate

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Immunoconjugate bound to its epitope (black)

An immunoconjugate (synonym antibody conjugate ) describes an antibody , an antibody fragment or an antibody mimetic that is linked by a covalent bond (conjugation) to a second functional molecule as a molecular marker . The second functional molecule can be, for example, a reporter enzyme , a medicinal substance , a radionuclide or a fluorescent marker .

functionality

How an antibody-toxin conjugate works

Immunoconjugates are used in biochemistry for the immunolabeling of biomolecules or in the therapy of cancer as chemoimmunoconjugates (synonym antibody-drug conjugate ). The coupling of a molecule to the antibodies takes place in the course of a molecule marking. With the help of the antibody, antibody fragment or antibody mimic, a selective binding to a specific target structure ( target ) of a cell or a molecule is achieved. TBS-T buffer is mostly used in biochemistry as a buffer for binding antibodies or immunoconjugates . The target of the antibody can, for example, be a tumor cell that presents a specific antigen on its surface . The conjugated functional molecule can - in the case of a therapeutic application - be, for example, a toxin which can develop a cytotoxic effect at its destination . Due to the (ideally) selective connection to the target structure, the active ingredient is only released at the desired location. Healthy cells are largely spared. It is a special form of drug targeting .

Radionuclides such as 90 yttrium , a β emitter, can also be used in therapeutic applications . In this case one speaks of radioimmunoconjugates or radioimmunotherapy . The radionuclides are mostly bound to the antibody via strong complexing agents such as DOTA , DTPA or TTHA . The short range of β-radiation means that only cells in the immediate vicinity of the immunoconjugates can be damaged.

Radioimmunoconjugates can also be used for purely diagnostic purposes. In these cases, short-lived, strong γ-emitters , such as 99m technetium , for single-photon emission computed tomography or positron emitters such as 68 gallium for positron emission tomography ("Immuno-PET") are conjugated to antibodies via complexing agents. In this way, for example, the course of therapy and possibly metastatisation can be tracked or diagnosed in patients . Conjugates of fluorescent dyes with antibodies can also be used in the field of diagnostics . These immunoconjugates are mainly used in preclinical studies and for pure research purposes. Radiolabeled antibodies are also used in a radioimmunoassay .

In biochemical analysis, reporter enzyme-coupled immunoconjugates are used in various detection methods for signal amplification (e.g. in ELISA , ELISPOT , Western blot and immunohistochemistry ), sometimes also as double immune labeling .

Antibodies modified by a fluorescent label are used in immunofluorescence microscopy , fluorimetry and flow cytometry .

If cytokines are bound to an antibody or an antibody fragment, one speaks of an immune cytokine .

Manufacturing

During production, the crosslinkers between the antibody and a reporter molecule are chosen in such a way that the binding of the antibody to its target antigen is not greatly reduced and the function of the reporter molecule is not impaired. Subsequent size exclusion chromatography separates the conjugate from uncrosslinked antibodies and reporter molecules, which competitively inhibit subsequent binding to the antigen or produce a background color.

Examples

Gemtuzumab ozogamicin is an immunoconjugate approved in the United States for the treatment of acute myeloid leukemia consisting of a monoclonal antibody directed against the CD-33 antigen and a bacterial toxin. It was approved in the United States in 2000 as the first antibody-toxin conjugate .

Ibritumomab-Tiuxetan is an immunoconjugate made up of the monoclonal antibody Ibritumomab and the complexing agent Tiuxetan (a DTPA derivative ), which is loaded with 90 yttrium immediately before its application . It is approved for the treatment of various malignant lymphomas of B lymphocytes ( radioimmunotherapy ).

Tositumomab , a murine monoclonal antibody labeled with 131 iodine , is approved for the treatment of non-Hodgkin lymphomas .

Arcitumomab is an antibody fragment (a Fab fragment ) which is against the carcinoembryonic antigen is addressed, which is primarily of colorectal carcinomas expressed is. Arcitumomab is loaded with 99m technetium immediately prior to injection into the patient . With the help of SPECT, the carcinoma can then be localized or the extent of remission or possible metastasis can be visualized.

literature

Individual evidence

  1. ^ RJ Kreitman: Immunotoxins for targeted cancer therapy. In: AAPS J 8, 2006, pp. 532-551. PMID 17025272 (Review)
  2. ↑ PM Deckert: Current constructs and targets in clinical development for antibody-based cancer therapy. In: Curr Drug Targets 10, 2009, pp. 158-175. PMID 19199912 (Review)
  3. ↑ MJ Koppe et al: Antibody-guided radiation therapy of cancer. In: Cancer Metastasis Rev 24, 2005, pp. 539-567. PMID 16408161 (Review)
  4. ^ DM Goldenberg and RM Sharkey: Novel radiolabeled antibody conjugates. In: Oncogene 26, 2007, pp. 3734-3744. PMID 17530026 (Review)
  5. ↑ MJ Merino et al: Monoclonal antibodies for radioimmunoscintigraphy of breast cancer. In: Int J Rad Appl Instrum B 18, 1991, pp. 437-443. PMID 1650767 (Review)
  6. ↑ E. Stipsanelli and P. Valsamaki: Monoclonal antibodies: old and new trends in breast cancer imaging and therapeutic approach. In: Hell J Nucl Med 8, 2005, pp. 103-108. PMID 16142251
  7. ^ I. Verel et al: The promise of immuno-PET in radioimmunotherapy. In: J Nucl Med 46, 2005, pp. 164S-171S. PMID 15653665 (Review)
  8. ↑ SJ DeNardo: Radioimmunodetection and therapy of breast cancer. In: Semin Nucl Med 35, 2005, pp. 143-151. PMID 15765377 (Review)
  9. ^ RA Reisfeld et al.: Immunocytokines: a new approach to immunotherapy of melanoma. In: Melanoma Res 7, 1997, pp. 99-106. PMID 9578424 (Review)
  10. ^ A b R. M. Sharkey and DM Goldenberg: Perspectives on cancer therapy with radiolabeled monoclonal antibodies. In: J Nucl Med 46, 2005, pp. 115S-127S. PMID 15653660 (Review)