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A '''bispecific monoclonal antibody''' ('''BsMAb''', '''BsAb''') is an artificial [[protein]] that is composed of fragments of two different [[monoclonal antibodies]] and consequently binds to two different types of [[antigen]]. The most widely used application of this approach is in [[cancer immunotherapy]], where BsMAbs are engineered that simultaneously bind to a [[cytotoxic]] cell (using a receptor like [[CD3 receptor|CD3]]) and a target like a [[tumour]] cell to be destroyed.<ref>Mueller, D; Kontermann, RE (2010). "Bispecific antibodies for cancer immunotherapy. " Biodrugs 24(2): 89-98. PMID 20199124</ref>
A '''bispecific monoclonal antibody''' ('''BsMAb''', '''BsAb''') is an artificial [[protein]] that is composed of fragments of two different [[monoclonal antibodies]] and consequently binds to two different types of [[antigen]]. The most widely used application of this approach is in [[cancer immunotherapy]], where BsMAbs are engineered that simultaneously bind to a [[cytotoxic]] cell (using a receptor like [[CD3 receptor|CD3]]) and a target like a [[tumour]] cell to be destroyed. <ref name="Mueller" /> <ref name="Chames" />
<ref>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</ref>
==Structure==
==Structure==
[[File:Engineered monoclonal antibodies.svg|thumb|350px|Three types of bispecific antibodies: [[trifunctional antibody]], [[chemically linked Fab]] and [[bi-specific T-cell engager]] (bottom row). Parts of the two different antibodies are coloured blue and green, respectively.]]
[[File:Engineered monoclonal antibodies.svg|thumb|350px|Three types of bispecific antibodies: [[trifunctional antibody]], [[chemically linked Fab]] and [[bi-specific T-cell engager]] (bottom row). Parts of the two different antibodies are coloured blue and green, respectively.]]
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==References==
==References==
{{reflist|refs=
{{reflist|refs=
<ref>Mueller, D; Kontermann, RE (2010). "Bispecific antibodies for cancer immunotherapy." ''Biodrugs'' '''24'''(2): 89-98. PMID 20199124</ref>
<ref name="Mueller">{{cite journal|last1=Mueller|first1=D|last2=Kontermann|first2=RE|date=2010|title=Bispecific antibodies for cancer immunotherapy|journal=Biodrugs|volume=24|issue=2|pages=89-98|pmid=20199124}}</ref>
<ref>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</ref>
<ref name="Chames">{{cite journal|last1=Chames|first1=P|last2=Baty|first2=D|date=2009|title=Bispecific antibodies for cancer therapy: The light at the end of the tunnel.|journal=mAbs|volume=1|issue=6|pages=1-9|pmid=20073127}}</ref>
<ref name="Lindhofer">{{cite journal|last1=Lindhofer|first1=H|last2=Mocikat|first2=R|last3=Steipe|first3=B|last4=Thierfelder|first4=S|date=1 July 1995|title=Preferential species-restricted heavy/light chain pairing in rat/mouse quadromas. Implications for a single-step purification of bispecific antibodies|journal=Journal of Immunology|publisher=Journal of Immunology|volume=155|issue=1|pages=219–225|url=http://www.jimmunol.org/cgi/content/abstract/155/1/219|pmid=7602098}}</ref>
<ref name="Lindhofer">{{cite journal|last1=Lindhofer|first1=H|last2=Mocikat|first2=R|last3=Steipe|first3=B|last4=Thierfelder|first4=S|date=1 July 1995|title=Preferential species-restricted heavy/light chain pairing in rat/mouse quadromas. Implications for a single-step purification of bispecific antibodies|journal=Journal of Immunology|publisher=Journal of Immunology|volume=155|issue=1|pages=219–225|url=http://www.jimmunol.org/cgi/content/abstract/155/1/219|pmid=7602098}}</ref>
<ref name="Baeuerle">{{cite journal|last1=Baeuerle|first1=PA|last2=Reinhardt|first2=C|url=http://cancerres.aacrjournals.org/cgi/content/full/69/12/4941|title=Bispecific T-cell engaging antibodies for cancer therapy|journal=Cancer Res|volume=69|year=2009|pages=4941–4944|pmid=19509221|doi=10.1158/0008-5472.CAN-09-0547|issue=12}}</ref>
<ref name="Baeuerle">{{cite journal|last1=Baeuerle|first1=PA|last2=Reinhardt|first2=C|url=http://cancerres.aacrjournals.org/cgi/content/full/69/12/4941|title=Bispecific T-cell engaging antibodies for cancer therapy|journal=Cancer Res|volume=69|year=2009|pages=4941–4944|pmid=19509221|doi=10.1158/0008-5472.CAN-09-0547|issue=12}}</ref>

Revision as of 13:48, 26 May 2011

A bispecific monoclonal antibody (BsMAb, BsAb) is an artificial protein that is composed of fragments of two different monoclonal antibodies and consequently binds to two different types of antigen. The most widely used application of this approach is in cancer immunotherapy, where BsMAbs are engineered that simultaneously bind to a cytotoxic cell (using a receptor like CD3) and a target like a tumour cell to be destroyed. [1] [2]

Structure

Three types of bispecific antibodies: trifunctional antibody, chemically linked Fab and bi-specific T-cell engager (bottom row). Parts of the two different antibodies are coloured blue and green, respectively.

In order to overcome manufacturing difficulties a first-generation BsMAb, called trifunctional antibody, has been developed consisting of two heavy and two light chains, one each from two different antibodies. The two Fab regions (the arms) are directed against two antigens. The Fc region (the foot) is made up from the two heavy chains and forms the third binding site; hence the name.[3]

Other types of bispecific antibodies have been designed to overcome certain problems, such as short half-life, immunogenicity and side-effects caused by cytokine liberation. They include chemically linked Fabs, consisting only of the Fab regions, and various types of bivalent and trivalent single-chain variable fragments (scFvs), fusion proteins mimicking the variable domains of two antibodies. The furthest developed of these newer formats are the bi-specific T-cell engagers (BiTEs).[4]

Mechanism of action

The mechanism of action of a BsMAb, exemplified by catumaxomab

The mechanism of acion of a BsMAb, exemplified by catumaxomab representing the first approved bispecific trifunctional antibody. Of the two paratopes that form the tops of the variable domains, one can be directed against a tumour antigen and the other against a T-lymphocyte antigen like CD3. In the case of trifunctional antibodies, the Fc region additionally binds to a cell that expresses Fc receptors, like a macrophage, a natural killer cell or a dendritic cell. In sum, the tumour cell is connected to one or two cells of the immune system, which subsequently destroy it.[3][4]

Advantages over ordinary monoclonal antibodies

Cancer immunotherapy with ordinary monoclonal antibodies does not activate T-lymphocytes because this type of cell does not possess Fc receptors, so the Fc region cannot bind to them, and the Fab regions are already used for binding the tumour cells.[5] Bispecific antibodies have a higher cytotoxic potential. They bind to antigens that are expressed relatively weakly.[6] The effective dose is around 0.01 mg·m−2·d−1 (milligrams per square metre body surface area per day), several orders of magnitude lower than with ordinary antibodies.[5]

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. ^ a b Lindhofer, H; Mocikat, R; Steipe, B; Thierfelder, S (1 July 1995). "Preferential species-restricted heavy/light chain pairing in rat/mouse quadromas. Implications for a single-step purification of bispecific antibodies". Journal of Immunology. 155 (1). Journal of Immunology: 219–225. PMID 7602098.
  4. ^ a b Baeuerle, PA; Reinhardt, C (2009). "Bispecific T-cell engaging antibodies for cancer therapy". Cancer Res. 69 (12): 4941–4944. doi:10.1158/0008-5472.CAN-09-0547. PMID 19509221.
  5. ^ a b Bargou, R; Leo, E; Zugmaier, G; Klinger, M; Goebeler, M; Knop, S; Noppeney, R; Viardot, A; Hess, G (2008). "Tumor regression in cancer patients by very low doses of a T cell-engaging antibody". Science. 321 (5891): 974–7. doi:10.1126/science.1158545. PMID 18703743.
  6. ^ 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.

Further reading

  • Morrison, SL (2007). "Two heads are better than one". Nature biotechnology. 25 (11): 1233–4. doi:10.1038/nbt1107-1233. PMID 17989683.
  • Fischer, N; Léger, O (2007). "Bispecific antibodies: molecules that enable novel therapeutic strategies". Pathobiology : journal of immunopathology, molecular and cellular biology. 74 (1): 3–14. doi:10.1159/000101046. PMID 17496428.
  • Marvin, JS; Zhu, Z (2005). "Recombinant approaches to IgG-like bispecific antibodies". Acta pharmacologica Sinica. 26 (6): 649–58. doi:10.1111/j.1745-7254.2005.00119.x. PMID 15916729.
  • Dincq, S; Bosman, F; Buyse, MA; Degrieck, R; Celis, L; De Boer, M; Van Doorsselaere, V; Sablon, E (2001). "Expression and purification of monospecific and bispecific recombinant antibody fragments derived from antibodies that block the CD80/CD86-CD28 costimulatory pathway". Protein expression and purification. 22 (1): 11–24. doi:10.1006/prep.2001.1417. PMID 11388794.

External links

Public Domain This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute.

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