Trifunctional antibody

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 accessory cells like 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]

At an equivalent dose a trifunctional antibody is more potent (more than 1,000-fold) in eliminating tumor cells than conventional antibodies.[2] 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. These trifunctional antibodies also 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.[3][4] Furthermore, putative cancer stem cells from malignant ascites fluid were eliminated due to catumaxomab treatment.[5]

Catumaxomab, was the first to be approved for clinical use (in 2009 for the treatment of malignant ascites in cancer patients).

Examples include catumaxomab (EpCAM / CD3),[6][7] ertumaxomab (HER2/neu / CD3),[8] FBTA05 (CD20 / CD3, proposed trade name Lymphomun)[9][10] and TRBS07 (GD2 / CD3, proposed trade name Ektomab),[11] drugs against various types of cancer.

  1. ^ Chames, P; Baty, D (2009). "Bispecific antibodies for cancer therapy: the light at the end of the tunnel". mAbs. 1 (6): 1–9. doi:10.4161/mabs.1.6.10015. PMC 2791310. PMID 20073127.
  2. ^ Jäger M, Schoberth A, Ruf P, Hess J, Lindhofer H (2009). "The trifunctional antibody ertumaxomab destroys tumor cells that express low levels of human epidermal growth factor receptor". Cancer Research. 69 (10): 4270–4276. doi:10.1158/0008-5472.CAN-08-2861. PMID 19435924.
  3. ^ 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): 2601. doi:10.1200/jco.2011.29.15_suppl.2601.
  4. ^ 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): 2575. doi:10.1200/jco.2011.29.15_suppl.2575.
  5. ^ 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): 3014. doi:10.1200/jco.2009.27.15_suppl.3014.
  6. ^ 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.
  7. ^ Sebastian M, Passlick B, Friccius-Quecke H, Jäger M, Lindhofer H, Kanniess F, 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. doi:10.1007/s00262-007-0310-7. PMC 11030102. PMID 17410361. S2CID 9817411.
  8. ^ Kiewe P, Hasmüller S, Kahlert S, Heinrigs M, Rack B, Marmé A, Korfel A, Jäger M, 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. doi:10.1158/1078-0432.CCR-05-2436. PMID 16707606.
  9. ^ Buhmann R, Simoes B, Stanglmaier M, Yang T, Faltin M, Bund D, Lindhofer H, Kolb HJ, 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. doi:10.1038/bmt.2008.323. PMID 18850012.
  10. ^ Boehrer, Simone; Schroeder, Petra; Mueller, Tina; Atz, Judith; Chow, Kai Uwe (2011). "Cytotoxic effects of the trifunctional bispecific antibody FBTA05 in ex-vivo cells of chronic lymphocytic leukaemia depend on immune-mediated mechanism". Anti-Cancer Drugs. 22 (6): 519–530. doi:10.1097/CAD.0b013e328344887f. ISSN 0959-4973. PMID 21637160. S2CID 29327089.
  11. ^ Ruf P, Jäger M, Ellwart J, Wosch S, Kusterer E, Lindhofer H (2004). "Two new trifunctional antibodies for the therapy of human malignant melanoma". International Journal of Cancer. 108 (5): 725–32. doi:10.1002/ijc.11630. PMID 14696099.