Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Dec 1;9(4):68.
doi: 10.3390/antib9040068.

Complement Activation in the Treatment of B-Cell Malignancies

Clive S Zent  1 , Jonathan J Pinney  2   3 , Charles C Chu  1 , Michael R Elliott  2   3
Affiliations
Review

Complement Activation in the Treatment of B-Cell Malignancies

Clive S Zent et al. Antibodies (Basel). .

Abstract

Unconjugated monoclonal antibodies (mAb) have revolutionized the treatment of B-cell malignancies. These targeted drugs can activate innate immune cytotoxicity for therapeutic benefit. mAb activation of the complement cascade results in complement-dependent cytotoxicity (CDC) and complement receptor-mediated antibody-dependent cellular phagocytosis (cADCP). Clinical and laboratory studies have showed that CDC is therapeutically important. In contrast, the biological role and clinical effects of cADCP are less well understood. This review summarizes the available data on the role of complement activation in the treatment of mature B-cell malignancies and proposes future research directions that could be useful in optimizing the efficacy of this important class of drugs.

Keywords: B-cell lymphoma; chronic lymphocytic leukemia (CLL); complement; cytotoxicity; monoclonal antibody; phagocytosis.

PubMed Disclaimer

Conflict of interest statement

C.S.Z. and C.C.C.: research funding from Acerta/AstraZeneca and TG Therapeutics.

Figures

Figure 1
Figure 1
Overview of cytotoxic mechanisms underlying mAb-mediated complement fixation. Depiction of type I anti-CD20 mAb binding to surface of target cells. Complement-dependent cytotoxicity (CDC) occurs following formation and binding of multiple copies of the membrane attack complex (MAC) on the target cell surface downstream of mAb-induced initiation of the complement cascade. Target cell killing by complement receptor-mediated antibody-dependent cellular phagocytosis (cADCP) results from mAb-mediated deposition and covalent binding of C3 activation fragments to the cell surface, which are in turn recognized by complement receptors (CR3 is shown) which trigger activation of phagocytic pathways in phagocytes such as macrophages.
Figure 2
Figure 2
Anti-CD20 monoclonal antibody (mAb) ligation and activation of complement. (A) CD20 molecules form homodimers in the B-cell membrane. Rituximab (RTX) and obinutuzumab (OBI) ligate the long extracellular loop (ECL). RTX binds the long ECL in an area near the short ECL. OBI binds the long ECL in an area away from the short ECL. Ofatumumab (OFA) ligates the short ECL of the CD20 molecule. Type I complement-activating anti-CD20 mAb (RTX and OFA) Fabs can bind to two adjacent CD20 dimers. In contrast, the non-complement-activating anti-CD20 OBI binds only one CD20 dimer, resulting in a different Fc orientation to type I mAbs. (B) Model of the extracellular view from the top showing that type I anti-CD20 mAb RTX and OFA ligate adjacent CD20 dimers to form a hexamer that efficiently activates C1q.
See this image and copyright information in PMC

References

    1. Coiffier B., Lepage E., Brière J., Herbrecht R., Tilly H., Bouabdallah R., Morel P., Neste E.V.D., Salles G., Gaulard P., et al. CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma. N. Engl. J. Med. 2002;346:235–242. doi: 10.1056/NEJMoa011795. - DOI - PubMed
    1. Habermann T.M., Weller E.A., Morrison V.A., Gascoyne R.D., Cassileth P.A., Cohn J.B., Dakhil S.R., Woda B., Fisher R.I., Peterson B.A., et al. Rituximab-CHOP Versus CHOP Alone or with Maintenance Rituximab in Older Patients with Diffuse Large B-Cell Lymphoma. J. Clin. Oncol. 2006;24:3121–3127. doi: 10.1200/JCO.2005.05.1003. - DOI - PubMed
    1. Marcus R., Imrie K., Belch A., Cunningham D., Flores E., Catalano J., Solal-Celigny P., Offner F., Walewski J., Raposo J., et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005;105:1417–1423. doi: 10.1182/blood-2004-08-3175. - DOI - PubMed
    1. Schulz H., Bohlius J.F., Trelle S., Skoetz N., Reiser M., Kober T., Schwarzer G., Herold M., Dreyling M., Hallek M., et al. Immunochemotherapy with Rituximab and Overall Survival in Patients with Indolent or Mantle Cell Lymphoma: A Systematic Review and Meta-analysis. J. Natl. Cancer Inst. 2007;99:706–714. doi: 10.1093/jnci/djk152. - DOI - PubMed
    1. Hallek M., Fischer K., Fingerle-Rowson G., Fink A.M., Busch R., Mayer J., Hensel M., Hopfinger G., Hess G., Von Grünhagen U., et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: A randomised, open-label, phase 3 trial. Lancet. 2010;376:1164–1174. doi: 10.1016/S0140-6736(10)61381-5. - DOI - PubMed

LinkOut - more resources