Bispecific antibody

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A bispecific antibody (abbreviation: BsMAb from English bispecific monoclonal antibody ), also known as a hybrid antibody , is an immunoconjugate that is made up of components from two different monoclonal antibodies . Bispecific antibodies are a potential therapeutic concept in cancer immunotherapy and are the subject of clinical studies .

Structure and mechanism of action

Schematic representation of various antibodies and antibody fragments. Of the six variants shown are Quadroma, chemically coupled Fab and BiTE bispecific antibodies.
Mechanism of action of a bispecific antibody using the example of a BiTE antibody.

A bispecific antibody of the first generation - also known as a quadroma - consists of a heavy and a light chain of two different monoclonal antibodies. The two arms of the antibody are directed against other antigens . The Fc part (the “foot” of the antibody) is formed together from the two heavy chains of the antibodies and represents the third binding site of the bispecific antibody. This structure enables the paratope of an antibody directed against a tumor antigen and the paratope, for example another antibody directed against a lymphocyte antigen, to be placed on each arm of the bispecific antibody. In this example it is then possible for the antibody to bind to a tumor cell with the corresponding tumor antigen and to a lymphocyte. Antigen- presenting cells such as B cells or macrophages can then bind via the Fc portion of the bispecific antibody and form a three-cell complex . This three-cell complex usually results in an improved activation of the body's own immune cells against the tumor cells.

The bispecific antibodies of the newer generation deviate from this structure. They can be made up of two scFv fragments (fragments of monoclonal antibodies). For example, an antibody directed at the CD3 antigen can thus also bind to T cells with the second paratope, with lower affinity, and only activate the T cell when it binds to the tumor cell with the CD3 antigen. In these cases, one speaks of bispecific antibodies for the recruitment of effector cells . This concept is called " BiTE " ( bispecific T-cell engager ).

Advantages over monoclonal antibodies

If a paratope is directed against T cells, these cells can also be activated. This is not possible with normal monoclonal antibodies because T cells do not have Fc receptors . Bispecific antibodies also have a higher cytotoxic potential. They also bind to antigens that are relatively weakly expressed . The necessary dose per patient is in the range of 0.01 mg · m −2 · d −1 and is several orders of magnitude lower than with monoclonal antibodies.

Manufacturing

Bispecific antibodies do not occur in normal living things, which is why they have to be produced artificially. The first concepts for bispecific antibodies date from the mid-1980s. As a result, the first bispecific antibodies were produced in an extremely complex manner, which considerably restricted the further development of this concept for many years. One of the methods is the fusion of two hybdridomas using the hybridoma technique (Quadroma technique). Another variant is the chemical coupling of two antibodies or antibody fragments.

With the help of genetic engineering , the synthesis of larger amounts of bispecific antibodies for therapeutic applications is now possible. In particular, the recombinant production of bispecific antibodies from antibody fragments is the currently established production method. A BiTE antibody can be produced recombinantly via four coding genes to a single protein with approximately 55  kDa molar mass .

Development status

The clinical results with the first generation of bispecific antibodies did not meet the initial expectations. The reason for this was the low effectiveness - partly because of the very short plasma half-life of the hybrid antibodies - and their immunogenicity . The Quadroma antibodies showed a therapeutic effect in some of the patients in initial clinical studies. The immunogenicity - due to the murine components of the bispecific antibody - led, however, to a human anti-mouse antibody response , with the release of HABA ( human anti-bispecific antibodies ). This ruled out prolonged treatment with bispecific antibodies. In addition, the Fc part of the Quadroma antibodies caused cross-linking with various Fc receptors, which resulted in a greatly increased release of cytokines and, as a result, severe side effects.

Better results - with fewer side effects - could be achieved with chemically linked bispecific Fab fragments. The clinical studies were quite promising. The complex and therefore very expensive manufacturing process ultimately meant that no more extensive clinical studies (phase III) were carried out. The interest in the concept of bispecific antibodies decreased noticeably in the following period.

First representative

Due to the development of the BiTE concept, the interest in bispecific antibodies has increased again considerably in recent years.

More candidates

Currently (as of 2017) there are at least two other BiTE antibodies in clinical development (phase III) :

  • Solitomab (MT110) from Amgen , directed against the antigens CD3 and EpCAM ( epithelial cell adhesion molecule ) and is said to be effective against bronchial and gastrointestinal cancers.
  • Emicizumab (ACE910) from Roche , for the treatment of haemophilia A (with inhibitors). Emicizumab was approved by the FDA in November 2017. Approval for Europe is still pending.

See also

literature

Reference books

Review article

  • P. Bühler, U. Elsässer-Beile: Bispecific antibodies and diabodies for cancer immunotherapy. In: Immunotherapy. Vol 4, No. 5, 2012, pp. 459-460. PMID 22642325
  • R. Repp et al. a .: Bispecific antibodies in hematology and oncology. In: Internist (Berl). , Volume 42, 2001, pp. 854-859. PMID 11449632
  • SL Morrison: Two heads are better than one. In: Nature Biotechnology , Volume 25, 2007, pp. 1233-1234. PMID 17989683
  • N. Fischer, O. Léger: Bispecific antibodies: molecules that enable novel therapeutic strategies. In: Pathobiology , Volume 74, 2007, pp. 3-14. PMID 17496428
  • JS Marvin, Z. Zhu: Recombinant approaches to IgG-like bispecific antibodies. In: Acta Pharmacol Sin . , Volume 26, 2005, pp. 649-658. PMID 15916729
  • MW Fanger u. a .: Production and use of anti-FcR bispecific antibodies. In: Immunomethods , Volume 4, 1994, pp. 72-81. PMID 8069530
  • P. Chames, D. Baty: Bispecific antibodies for cancer therapy. In: Curr Opin Drug Discov Devel. , Volume 12, 2009, pp. 276-283. PMID 19333873
  • MR Suresh et al. a .: Advantages of bispecific hybridomas in one-step immunocytochemistry and immunoassays. In: PNAS . Volume 83, 1986, pp. 7989-7993. PMID 2429324

Technical article

Web links

Individual evidence

  1. ↑ T. Dreier and a .: Extremely potent, rapid and costimulation-independent cytotoxic T-cell response against lymphoma cells catalyzed by a single-chain bispecific antibody. In: International Journal of Cancer . Volume 100, 2002, pp. 690-697. PMID 12209608
  2. ↑ K. Brischwein et al. a .: Strictly target cell-dependent activation of T cells by bispecific single-chain antibody constructs of the BiTE class. In: Journal of Immunotherapy . Volume 30, 2007, pp. 798-807. PMID 18049331
  3. ↑ a b c d C. Kellner: Development and characterization of bispecific antibody derivatives for the immunotherapy of CD19-positive leukemias and lymphomas. Dissertation. Friedrich-Alexander University Erlangen-Nuremberg, 2008.
  4. ^ PA Baeuerle, C. Reinhardt, P. Kufer: BiTE: A new class of antibodies that recruit T-cells . In: Drugs of the Future . tape 33 , no. 2 , 2008, p. 137–147 , doi : 10.1358 / dof.2008.033.02.1172578 .
  5. ↑ PA Baeuerle u. a .: BiTE: Teaching antibodies to engage T cells for cancer therapy. In: Curr Opin Mol Ther. Volume 11, 2009, pp. 22-30. PMID 19169956 (Review)
  6. ↑ a b P. A. Baeuerle, C. Reinhardt: Bispecific T-cell engaging antibodies for cancer therapy. In: Cancer Research . Volume 69, 2009, pp. 4941-4944. PMID 19509221 (Review)
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  8. ↑ a b M. Peipp, T. Valerius: Bispecific antibodies targeting cancer cells. In: Biochem Soc Trans . Volume 30, 2002, pp. 507-511. PMID 12196124 (Review)
  9. ↑ a b L. M. Weiner u. a .: Binding and cytotoxicity characteristics of the bispecific murine monoclonal antibody 2B1. In: J Immunol. Volume 151, 1993, pp. 2877-2886. PMID 8103070
  10. ↑ UD Staerz u. a .: Hybrid antibodies can target sites for attack by T cells. In: Nature . Volume 314, 1985, pp. 628-631. PMID 2859527
  11. ↑ P. Borchmann u. a .: Monoclonal Antibodies: Development and Clinical Perspectives. In: The internist. Volume 42, 2001, pp. 803-814. doi: 10.1007 / s001080170123 .
  12. ↑ MJ Glennie et al. a: Preparation and performance of bispecific F (ab 'gamma) 2 antibody containing thioether-linked Fab' gamma fragments. In: J Immunol. Volume 139, 1987, pp. 2367-2375. PMID 2958547
  13. ↑ B. Karpovsky et al. a .: Production of target-specific effector cells using hetero-cross-linked aggregates containing anti-target cell and anti-Fc gamma receptor antibodies. In: J Exp Med . Volume 160, 1984, pp. 1686-1701. PMID 6239899
  14. ↑ C. Milstein, AC Cuello: Hybrid hybridomas and their use in immunohistochemistry. In: Nature. Volume 305, 1983, pp. 537-540. PMID 6137772
  15. ↑ D. Schrama et al. a .: Antibody targeted drugs as cancer therapeutics. In: Nat Rev Drug Discov . Volume 5, 2006, pp. 147-159. PMID 16424916
  16. ↑ MR Suresh et al. a .: Bispecific monoclonal antibodies from hybrid hybridomas. In: Methods Enzymol. Volume 121, 1986, pp. 210-228. PMID 3724461
  17. ^ I. Heisler: Importance of cleavable peptide linkers for the function of recombinant saporin-EGF immunotoxins . Berlin 2008, DNB  968622887 , urn : nbn: de: kobv: 188-2003002108 (dissertation).
  18. ^ A b R. T. Curnow: Clinical experience with CD64-directed immunotherapy. An overview. In: Cancer Immunol Immunother . Volume 45, 1997, pp. 210-215. PMID 9435876 (Review)
  19. ↑ S. Canevari et al. a .: Bispecific antibody targeted T cell therapy of ovarian cancer: clinical results and future directions. In: J Hematother. Volume 4, 1995, pp. 423-427. PMID 8581379
  20. ↑ CH Lamers u. a .: Local but no systemic immunomodulation by intraperitoneal treatment of advanced ovarian cancer with autologous T lymphocytes re-targeted by a bi-specific monoclonal antibody. In: Int J Cancer . Volume 73, 1997, pp. 211-219. PMID 9335445
  21. ↑ DM Segal u. a .: Bispecific antibodies in cancer therapy. In: Curr Opin Immunol . Volume 11, 1999, pp. 558-562. PMID 10508714 (Review)
  22. ↑ F. Hartmann u. a .: Treatment of refractory Hodgkin's disease with an anti-CD16 / CD30 bispecific antibody. In: Blood . Volume 89, 1997, pp. 2042-2047. PMID 9058726
  23. ↑ LM Weiner u. a .: Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. In: Cancer Res . Vol. 55, 1995, pp. 4586-4593. PMID 7553634
  24. ↑ BK Link u. a .: Anti-CD3-based bispecific antibody designed for therapy of human B-cell malignancy can induce T-cell activation by antigen-dependent and antigen-independent mechanisms. In: Int J Cancer. Volume 77, 1998, pp. 251-256. PMID 9650561
  25. ↑ P. Borchmann u. a .: Phase 1 trial of the novel bispecific molecule H22xKi-4 in patients with refractory Hodgkin lymphoma. In: Blood . Volume 100, 2002, pp. 3101-3107. PMID 12384405
  26. ↑ ND James et al. a .: A phase II study of the bispecific antibody MDX-H210 (anti-HER2 x CD64) with GM-CSF in HER2 + advanced prostate cancer. In: Br J Cancer. Volume 85, 2001, pp. 152-156. PMID 11461069
  27. ↑ YES Posey et al. a .: A pilot trial of GM-CSF and MDX-H210 in patients with erbB-2-positive advanced malignancies. In: J Immunother. Volume 22, 1999, pp. 371-379. PMID 10404439
  28. ↑ FH Valone u. a .: Phase Ia / Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the proto-oncogene HER-2 / neu. In: J Clin Oncol . Volume 13, 1995, pp. 2281-2292. PMID 7545221
  29. ↑ Approval of Removab® (entry at EMA)
  30. ↑ FDA Grants Full Approval for BLINCYTO® (blinatumomab) to Treat Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia in Adults and Children . Press release Amgen, July 11, 2017, accessed on July 13, 2017.
  31. ↑ K. Brischwein et al. a .: MT110: a novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors. In: Mol Immunol. Volume 43, 2006, pp. 1129-1143. PMID 16139892
  32. ↑ Caroline Helwick: Novel BiTE antibody mediates contact between T cells and cancer cells . In: Oncology NEWS International . tape 17 , no. 6 , June 1, 2008 ( cancernetwork.com ).
  33. ↑ NCT00635596 Phase I Study of MT110 in Colorectal Cancer (CRC), Gastrointestinal (GI) and Lung Cancer (MT110-101) ClinicalTrials.gov
  34. ↑ M. Amann, S. d'Argouges, G. Lorenczewski, K. Brischwein, R. Kischel, R. Lutterbuese, S. Mangold, D. Rau, J. Volkland, S. Pflanz, T. Raum, M. Münz , P. Kufer, B. Schlereth, PA Baeuerle, M. Friedrich: Antitumor Activity of an EpCAM / CD3-bispecific BiTE Antibody During Long-term Treatment of Mice in the Absence of T-cell Anergy and Sustained Cytokine Release . In: Journal of Immunotherapy . tape 32 , no. 5 , 2009, p. 452-464 , doi : 10.1097 / CJI.0b013e3181a1c097 , PMID 19609237 .
  35. ↑ Positive phase III results for Roche's emicizumab in haemophilia A published in The New England Journal of Medicine . Press release Roche, July 10, 2017; accessed on July 13, 2017.
  36. ↑ Roche's Hemlibra Significantly reduced bleeds into phase III study in haemophilia A . Press release Roche, November 20, 2017; accessed on November 22, 2017.
  37. ↑ FDA approves new treatment to prevent bleeding in patients with hemophilia A Certain . Press release FDA, November 16, 2017; accessed on November 22, 2017.
  38. ↑ FDA approves Roche's Hemlibra (emicizumab-kxwh) for haemophilia A with inhibitors . Press release Roche, November 16, 2017; accessed on November 22, 2017.