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At an equivalent dose a trifunctional antibody is more potent (> 1,000-fold) in eliminating tumor cells than conventional antibodies.<ref>{{cite journal | last1=Jaeger | first1=M | last2=et | first2=al. | title=The trifunctional antibody ertumaxomab destroys tumor cells that express low levels of human epidermal growth factor receptor| journal=Cancer Research | volume=69 | issue=10 | pages=4270-4276 | year=2009 | pmid=19435924 }}</ref> These drugs evoke the removal of tumor cells by means of (i) [[antibody-dependent cell-mediated cytoxicity]], a process also described for conventional antibodies and more importantly by (ii) polyclonal cytotoxic T cell responses with emphasis on CD8 T cells. Interestingly, these trifunctional antibodies elicit individual anti-tumor immune responses in cancer patients treated with e.g. catumaxomab; i.e. autologous antibodies as well as CD4 and CD8 T cells directed against the tumor were detected. <ref>{{cite journal | last1=Reinhard | first1=H | last2=et | first2=al. | title=The effect of trifunctional anti-EpCAM antibody catumaxomab on the development of tumor-specific immune responses in patients with gastric cancer | journal=Journal of Clinical Oncology | volume=29 | issue=suppl abstr 2601| year=2011 | url=http://abstract.asco.org/AbstView_102_82824.html }} </ref> <ref>{{cite journal | last1=Ruf | first1=P | last2=et | first2=al. | title=Humoral tumor-associated immune responses induced by catumaxomab in patients with malignant ascites | journal=Journal of Clinical Oncology | volume=29 | issue=suppl abstr 2575| year=2011 | url=http://abstract.asco.org/AbstView_102_81293.html}}</ref>. Furthermore, it should be noted that putative [[cancer stem cell]]s from malignant ascites fluid were eliminated due to catumaxomab treatment. <ref>{{cite journal | last1=Lindhofer| first1=H | last2=et | first2=al. | title= Elimination of cancer stem cells (CD133+/EpCAM+) from malignant ascites by the trifunctional antibody catumaxomab: results from a pivotal phase II/III study| journal=Journal of Clinical Oncology | volume=27 | issue=15s suppl abstr 3014| year=2009 | url=http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=32658 }}</ref>
At an equivalent dose a trifunctional antibody is more potent (> 1,000-fold) in eliminating tumor cells than conventional antibodies.<ref>{{cite journal | last1=Jaeger | first1=M | last2=et | first2=al. | title=The trifunctional antibody ertumaxomab destroys tumor cells that express low levels of human epidermal growth factor receptor| journal=Cancer Research | volume=69 | issue=10 | pages=4270-4276 | year=2009 | pmid=19435924 }}</ref> These drugs evoke the removal of tumor cells by means of (i) [[antibody-dependent cell-mediated cytoxicity]], a process also described for conventional antibodies and more importantly by (ii) polyclonal cytotoxic T cell responses with emphasis on CD8 T cells. Interestingly, these trifunctional antibodies elicit individual anti-tumor immune responses in cancer patients treated with e.g. catumaxomab; i.e. autologous antibodies as well as CD4 and CD8 T cells directed against the tumor were detected. <ref>{{cite journal | last1=Reinhard | first1=H | last2=et | first2=al. | title=The effect of trifunctional anti-EpCAM antibody catumaxomab on the development of tumor-specific immune responses in patients with gastric cancer | journal=Journal of Clinical Oncology | volume=29 | issue=suppl abstr 2601| year=2011 | url=http://abstract.asco.org/AbstView_102_82824.html }} </ref> <ref>{{cite journal | last1=Ruf | first1=P | last2=et | first2=al. | title=Humoral tumor-associated immune responses induced by catumaxomab in patients with malignant ascites | journal=Journal of Clinical Oncology | volume=29 | issue=suppl abstr 2575| year=2011 | url=http://abstract.asco.org/AbstView_102_81293.html}}</ref>. Furthermore, it should be noted that putative [[cancer stem cell]]s from malignant ascites fluid were eliminated due to catumaxomab treatment. <ref>{{cite journal | last1=Lindhofer| first1=H | last2=et | first2=al. | title= Elimination of cancer stem cells (CD133+/EpCAM+) from malignant ascites by the trifunctional antibody catumaxomab: results from a pivotal phase II/III study| journal=Journal of Clinical Oncology | volume=27 | issue=15s suppl abstr 3014| year=2009 | url=http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=32658 }}</ref>


Examples include [[catumaxomab]] ([[EpCAM]] / CD3) <ref>{{cite journal | last1=Shen| first1=J | last2=Zhu | first2=Z | title=Catumaxomab, a rat/murine hybrid trifunctional bispecific monoclonal antibody for the treatment of cancer | journal=Current Opinion in Molecular Therapeutics | volume=10 | issue=3| pages=273-284 | year=2008 | pmid=18535935}}</ref> <ref>{{cite journal | last1=Sebastian| first1=M | last2=et | first2=al. | title=Treatment of non-small cell lung cancer patients with the trifunctional monoclonal antibody catumaxomab (anti-EpCAM x anti-CD3): a phase I study| journal=Cancer Immunology Immunotherapy | volume=56 | issue=10| pages=1637-1644 | year=2007 | pmid=17410361}}</ref>,[[ertumaxomab]] ([[HER2/neu]] / CD3)<ref>{{cite journal | last1=Kiewe| first1=P | last2=et | first2=al. | title=Phase I trial of the trifunctional antibody anti-HER2/neu x anti-CD3 antibody ertumaxomab in metastatic breast cancer| journal=Clinical Cancer Research | volume=12 | issue=10| pages=3085-3091 | year=2006 | pmid=16707606}}</ref>, lymphomun ([[CD20]] / CD3) <ref>{{cite journal | last1=Buhmann| first1=R | last2=et | first2=al. | title=Immunotherapy of recurrent B–cell malignancies after allo SCT with Bi20 (FBTA05), a trifunctional anti-CD3 x anti-CD20 antibody and donor lymphocyte infusion| journal=Bone Marrow Transplantation | volume=43 | issue=5| pages=383-397 | year=2008 | pmid=18850012}}</ref> <ref>{{cite journal | last1=Boehrer| first1=S | last2=et | first2=al. | title= Cytotoxic effects of the trifunctional bispecific antibody FBTA05 in ex-vivo cells of chronic lymphocytic leukaemia depend on immune-mediated mechanisms | journal=Anti-Cancer Drugs |volume=12 | issue=10| pages=3085-3091 | year=2011 | url=http://journals.lww.com/anti-cancerdrugs/Abstract/publishahead/Cytotoxic_effects_of_the_trifunctional_bispecific.99702.aspx}}</ref> and ektomab ([[GD2]] / CD3) <ref>{{cite journal | last1=Ruf| first1=P | last2=et | first2=al. | title= Two new trifunctional antibodies for the therapy of human malignant melanoma | journal=International Journal of Cancer | volume=108 | pages=725-732 | year=2004 | pmid=14696099}}</ref>, drugs against various types of cancer.
Examples include [[catumaxomab]] ([[EpCAM]] / CD3) and [[ertumaxomab]] ([[HER2/neu]] / CD3), both drugs against various types of cancer.<ref>[http://www.fresenius.se/internet/fag/com/faginpub.nsf/Content/P-Info2004_01_15 Fresenius concentrates biotechnology activities on antibody and innovative cell therapies]</ref>


==History==
==History==

Revision as of 15:18, 26 May 2011

The mechanism of action of a trifunctional antibody, exemplified by catumaxomab

A trifunctional antibody is a monoclonal antibody with binding sites for two different antigens, typically CD3 and a tumor antigen, making it a type of bispecific monoclonal antibody. In addition, its intact Fc-part can bind to an Fc receptor on [cells] like other conventional monospecific antibodies. The net effect is that this type of drug links T cells (via CD3) and monocytes/macrophages, natural killer cells, dendritic cells or other Fc receptor expressing cells to the tumor cells, leading to their destruction.[1] [2]

At an equivalent dose a trifunctional antibody is more potent (> 1,000-fold) in eliminating tumor cells than conventional antibodies.[3] These drugs evoke the removal of tumor cells by means of (i) antibody-dependent cell-mediated cytoxicity, a process also described for conventional antibodies and more importantly by (ii) polyclonal cytotoxic T cell responses with emphasis on CD8 T cells. Interestingly, these trifunctional antibodies elicit individual anti-tumor immune responses in cancer patients treated with e.g. catumaxomab; i.e. autologous antibodies as well as CD4 and CD8 T cells directed against the tumor were detected. [4] [5]. Furthermore, it should be noted that putative cancer stem cells from malignant ascites fluid were eliminated due to catumaxomab treatment. [6]

Examples include catumaxomab (EpCAM / CD3) [7] [8],ertumaxomab (HER2/neu / CD3)[9], lymphomun (CD20 / CD3) [10] [11] and ektomab (GD2 / CD3) [12], drugs against various types of cancer.

History

Trifunctional antibodies were the first type of bispecific monoclonal antibodies to be produced. The first concepts date back to the mid-1980s.[13] For over twenty years, no such antibody was approved for clinical use, problems being a short elimination half-life,[14] immunogenicity,[15] and cross-linking with Fc receptors.[16] Immunogenicity results from the fact that the antibodies are obtained from rat and mice. After application, the patient's immune system usually produces human anti-mouse antibodies, which makes trifunctional antibodies unsuitable for long-term treatment.[17] Cross-linking leads to liberation of cytokines, resulting in severe adverse effects like fever, nausea and vomiting.[16]

Despite these problems, trifunctional antibodies can be suitable if only short-term use is required, and if lack of alternative drugs and the severity of the disease make the adverse effects acceptable. Catumaxomab, which was approved in 2009 for the treatment of malignant ascites in cancer patients, satisfies these conditions. It was the first, and as of July 2010 the only, of these antibodies in clinical use.

Another way of overcoming the problems of trifunctional antibodies is the exploration of bispecific antibodies with different structures. Notably, bi-specific T-cell engagers (BiTEs) have been produced since the mid-2000s.[18]

Production

At first, mouse hybridoma cells whose monoclonal antibodies target one of the desired antigens are produced. Independently, rat hybridoma cells targeting the other antigen are produced. These two cell types are hybridised, yielding hybrid-hybridomas or quadromas, which produce hybrid (trifunctional) antibody as well as pure mouse and pure rat antibody. The trifunctional antibody is extracted chromatographically with protein A.

Possible combinations of light and heavy chains in antibodies produced by quadroma cell lines. The seven antibodies on the left have at least one mismatched binding region. Of the three antibodies on the right, two are not hybridised, and the remaining (rightmost) is the desired trifunctional antibody. Mixed-species quadromas produce (nearly) none of the seven mismatched antibodies.

Using two different species (mouse and rat) has the advantage that less mismatched antibodies are produced because rat light chains preferably pair with rat heavy chains, and mouse light chains with mouse heavy chains. Single species (mouse/mouse or rat/rat) quadromas, by contrast, produce up to ten different kinds of antibody, most of which have mismatched heavy or light chains, or both.[19]

References

  1. ^ Mueller, D; Kontermann, RE (2010). "Bispecific antibodies for cancer immunotherapy". Biodrugs. 24 (2): 89–98. PMID 20199124.
  2. ^ Chames, P; Baty, D (2009). "Bispecific antibodies for cancer therapy: the light at the end of the tunnel". mAbs. 1 (6): 1–9. PMID 20073127.
  3. ^ Jaeger, M; et, al. (2009). "The trifunctional antibody ertumaxomab destroys tumor cells that express low levels of human epidermal growth factor receptor". Cancer Research. 69 (10): 4270–4276. PMID 19435924.
  4. ^ Reinhard, H; et, al. (2011). "The effect of trifunctional anti-EpCAM antibody catumaxomab on the development of tumor-specific immune responses in patients with gastric cancer". Journal of Clinical Oncology. 29 (suppl abstr 2601).
  5. ^ Ruf, P; et, al. (2011). "Humoral tumor-associated immune responses induced by catumaxomab in patients with malignant ascites". Journal of Clinical Oncology. 29 (suppl abstr 2575).
  6. ^ Lindhofer, H; et, al. (2009). "Elimination of cancer stem cells (CD133+/EpCAM+) from malignant ascites by the trifunctional antibody catumaxomab: results from a pivotal phase II/III study". Journal of Clinical Oncology. 27 (15s suppl abstr 3014).
  7. ^ Shen, J; Zhu, Z (2008). "Catumaxomab, a rat/murine hybrid trifunctional bispecific monoclonal antibody for the treatment of cancer". Current Opinion in Molecular Therapeutics. 10 (3): 273–284. PMID 18535935.
  8. ^ Sebastian, M; et, al. (2007). "Treatment of non-small cell lung cancer patients with the trifunctional monoclonal antibody catumaxomab (anti-EpCAM x anti-CD3): a phase I study". Cancer Immunology Immunotherapy. 56 (10): 1637–1644. PMID 17410361.
  9. ^ Kiewe, P; et, al. (2006). "Phase I trial of the trifunctional antibody anti-HER2/neu x anti-CD3 antibody ertumaxomab in metastatic breast cancer". Clinical Cancer Research. 12 (10): 3085–3091. PMID 16707606.
  10. ^ Buhmann, R; et, al. (2008). "Immunotherapy of recurrent B–cell malignancies after allo SCT with Bi20 (FBTA05), a trifunctional anti-CD3 x anti-CD20 antibody and donor lymphocyte infusion". Bone Marrow Transplantation. 43 (5): 383–397. PMID 18850012.
  11. ^ Boehrer, S; et, al. (2011). "Cytotoxic effects of the trifunctional bispecific antibody FBTA05 in ex-vivo cells of chronic lymphocytic leukaemia depend on immune-mediated mechanisms". Anti-Cancer Drugs. 12 (10): 3085–3091.
  12. ^ Ruf, P; et, al. (2004). "Two new trifunctional antibodies for the therapy of human malignant melanoma". International Journal of Cancer. 108: 725–732. PMID 14696099.
  13. ^ Staerz, UD; Kanagawa, O; Bevan, MJ (1985). "Hybrid antibodies can target sites for attack by T cells". Nature. 314 (6012): 628–31. doi:10.1038/314628a0. PMID 2859527.
  14. ^ Peipp, M; Valerius, T (2002). "Bispecific antibodies targeting cancer cells". Biochemical Society transactions. 30 (4): 507–11. doi:10.1042/BST0300507. PMID 12196124.
  15. ^ Curnow, RT (1997). "Clinical experience with CD64-directed immunotherapy. An overview". Cancer immunology, immunotherapy : CII. 45 (3–4): 210–5. doi:10.1007/s002620050435. PMID 9435876.
  16. ^ a b Weiner, LM; Holmes, M; Richeson, A; Godwin, A; Adams, GP; Hsieh-Ma, ST; Ring, DB; Alpaugh, RK (1993). "Binding and cytotoxicity characteristics of the bispecific murine monoclonal antibody 2B1". Journal of immunology (Baltimore, Md. : 1950). 151 (5): 2877–86. PMID 8103070.
  17. ^ Hartmann, F; Renner, C; Jung, W; Deisting, C; Juwana, M; Eichentopf, B; Kloft, M; Pfreundschuh, M (1997). "Treatment of refractory Hodgkin's disease with an anti-CD16/CD30 bispecific antibody". Blood. 89 (6): 2042–7. PMID 9058726.
  18. ^ Kufer, P; Lutterbüse, R; Baeuerle, PA (2004). "A revival of bispecific antibodies". Trends in biotechnology. 22 (5): 238–44. doi:10.1016/j.tibtech.2004.03.006. PMID 15109810.
  19. ^ Lindhofer, H; Mocikat, R; Steipe, B; Thierfelder, S (1995). "Preferential species-restricted heavy/light chain pairing in rat/mouse quadromas. Implications for a single-step purification of bispecific antibodies". Journal of immunology (Baltimore, Md. : 1950). 155 (1): 219–25. PMID 7602098.

Further reading

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