Immunocytokine

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Representation of different types of "armed antibodies". The immunocytokine at the top right

Immunocytokines (also spelled immunocytokines ) are antibody - cytokine - fusion proteins . They are immunoconjugates that represent a drug targeting approach in cancer immunotherapy for the treatment of cancer diseases . They are potential active ingredients that have not yet been approved . Some immune cytokines are in clinical trials against various types of cancer. This approach also has potential for treating other diseases.

One speaks in Immunzytokinen also armed antibodies ( english armed antibodies ).

Structure and working principle

Active substances can be bound (conjugated) to antibodies which, if freely administered systemically , would lead to unacceptable side effects due to their high toxicity . In this case, the antibody serves as a “transport vehicle” in order to bring the cytokine as specifically as possible only into the area of ​​the tumor cells. Some cytokines, for example interleukin-2 (IL-2), are highly potent active substances that can trigger a complex signal cascade to activate the body's own immune system . The side effects are considerable, however. With an antibody as a “ferry”, the side effects should be largely suppressed and the local concentration in the area of ​​the tumor cells should be as high as possible.

The conjugate of antibodies or an antibody fragment (for example an Fab fragment or a nanobody ) with a cytokine can be regarded as a prodrug .

The structure of antibodies and cytokines is the prerequisite for active as well as passive cancer immunotherapy, whereby both the innate as well as the acquired immune system can be activated to fight cancer.

synthesis

Immunocytokines are produced in a recombinant way using genetic engineering by introducing recombinant DNA into microorganisms such as Escherichia coli . With the aid of the polymerase chain reaction , the nucleotide sequences of the corresponding cytokine are generated after reverse transcription .

Potential uses

Some immune cytokines are currently in clinical trials in order to prove their effectiveness in humans. In most cases, interleukin-2, as well as α-interferon, are used as an active ingredient and a wide variety of antibodies or antibody fragments. Potential future applications include malignant melanoma , B-cell lymphomas , ovarian cancer and neuroblastoma in animal model efficacy against was breast cancer and pancreatic tumors detected.

Another potential non- oncological approach is the treatment of collagen-induced arthritis .

literature

  • R. Ronca et al. a .: Delivering cytokines at tumor site: The immunocytokine-conjugated anti-EDB-fibronectin antibody case. In: Immunobiology 214, 2009, pp. 800-810. PMID 19625102 (Review)
  • EE Johnson, HD Lum, AL Rakhmilevich, BE Schmidt, M. Furlong, IN Buhtoiarov, JA Hank, A. Raubitschek, D. Colcher, RA Reisfeld, SD Gillies, PM Sondel: Intratumoral immunocytokine treatment results in enhanced antitumor effects. In: Cancer Immunology, Immunotherapy , Volume 57, Number 12, December 2008, pp. 1891-1902, doi: 10.1007 / s00262-008-0519-0 , PMID 18438664 , PMC 2574976 (free full text).
  • M. Aigner: Production and functional analysis of immune cytokines containing interleukin-2 (IL-2) or granulocyte / macrophage colony-stimulating factor (GM-CSF) to improve an NDV-modified tumor vaccine. Dissertation, Heidelberg University, Faculty of Biosciences, 2006. urn : nbn: de: bsz: 16-opus-70268
  • JA Hank u. a .: Determination of peak serum levels and immune response to the humanized anti-ganglioside antibody-interleukin-2 immunocytokine. In: Methods Mol Med , 85, 2003, pp. 123-131. PMID 12710203 (Review)
  • HN Lode and RA Reisfeld: Immunocytokines for cancer immunotherapy. In: Die gelb Hefte , 39, 1999, pp. 43-50.
  • HN Lode u. a .: Immunocytokines: a promising approach to cancer immunotherapy. In: Pharmacol Ther , 80, 1998, pp. 277-292. PMID 9888698 (Review)
  • PM Sondel and JA Hank: Combination therapy with interleukin-2 and antitumor monoclonal antibodies. In: Cancer J Sci Am , 3, 1997, pp. 121-127. PMID 9457407 (Review)

Individual evidence

  1. ↑ D. Baron: Therapeutic use of monoclonal antibodies. In: Naturwissenschaften 84, 1997, pp. 189–198. doi: 10.1007 / s001140050376
  2. ^ GC MacDonald, N. Glover: Effective tumor targeting: strategies for the delivery of Armed Antibodies. In: Curr Opin Drug Discov Devel , 8, 2005, pp. 177-183. PMID 15782542 (Review)
  3. ↑ D. Schrama et al. a .: Antibody targeted drugs as cancer therapeutics. In: Nat Rev Drug Discov , 5, 2006, pp. 147-159. PMID 16424916
  4. ↑ S. Jaracz et al. a .: Recent advances in tumor-targeting anticancer drug conjugates. In: Bioorg. Med. Chem. , 13, 2005, pp. 5043-5054. PMID 15955702 (Review)
  5. ↑ HN Lode: Strategies for immunotherapy in neuroblastoma. Habilitation thesis, Charité Medical Faculty, Humboldt University Berlin, 2003
  6. ^ SD Gillies, EB Reilly, KM Lo, RA Reisfeld: Antibody-targeted interleukin 2 stimulates T-cell killing of autologous tumor cells. In: Proceedings of the National Academy of Sciences . Volume 89, Number 4, February 1992, pp. 1428-1432, PMID 1741398 , PMC 48464 (free full text).
  7. ^ RA Reisfeld u. a .: Immunocytokines: a new approach to immunotherapy of melanoma. In: Melanoma Res , 7, 1997, pp. 99-106. PMID 9578424 (Review)
  8. ↑ A. Ribas, JM Kirkwood, MB Atkins, TL Whiteside, W. Gooding, A. Kovar, SD Gillies, O. Kashala, MA Morse: Phase I / II open-label study of the biological effects of the interleukin-2 immunocytokine EMD 273063 (hu14.18-IL2) in patients with metastatic malignant melanoma. In: Journal of translational medicine , Volume 7, 2009, p. 68, doi: 10.1186 / 1479-5876-7-68 , PMID 19640287 , PMC 2724499 (free full text).
  9. ↑ C. Schliemann et al. a .: Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2. In: Blood , 113, 2009, pp. 2275-2283. PMID 19005180
  10. ↑ EA Rossi et al. a .: CD20-targeted tetrameric interferon-alpha, a novel and potent immunocytokine for the therapy of B-cell lymphomas. In: Blood , 114, 2009, pp. 3864-3871. PMID 19710501
  11. ↑ X. Zhang et al. a .: Development of an immunocytokine, IL-2-183B2scFv, for targeted immunotherapy of ovarian cancer. In: Gynecol Oncol , 103, 2006, pp. 848-852. PMID 16806435
  12. ↑ JA Hank u. a .: Immunogenicity of the hu14.18-IL2 immunocytokine molecule in adults with melanoma and children with neuroblastoma. In: Clin Cancer Res 15, 2009, pp. 5923-5930. PMID 19737959
  13. ↑ BH Yamane et al. a .: The development of antibody-IL-2 based immunotherapy with hu14.18-IL2 (EMD-273063) in melanoma and neuroblastoma. In: Expert Opin Investig Drugs , 18, 2009, pp. 991-1000. PMID 19548853 (Review)
  14. ↑ J. Mårlind et al. a .: Antibody-mediated delivery of interleukin-2 to the stroma of breast cancer strongly enhances the potency of chemotherapy. In: Clin Cancer Res , 14, 2008, pp. 6515-6524. PMID 18927291
  15. ↑ K. Wagner et al. a .: The targeted immunocytokine L19-IL2 efficiently inhibits the growth of orthotopic pancreatic cancer. In: Clin Cancer Res , 14, 2008, pp. 4951-4960. PMID 18676770
  16. ↑ K. Schwager, M. Kaspar, F. Bootz, R. Marcolongo, E. Paresce, D. Neri, E. Trachsel: Preclinical characterization of DEKAVIL (F8-IL10), a novel clinical-stage immunocytokine which inhibits the progression of collagen-induced arthritis. In: Arthritis research & therapy , Volume 11, Number 5, 2009, p. R142, doi: 10.1186 / ar2814 , PMID 19781067 , PMC 2787264 (free full text).