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The complement system is a group of approximately 20 plasma proteins that strengthen the body's defenses against infections through opsonization, inflammation, and cell lysis. Opsonization involves coating pathogens with complement proteins, making them more recognizable and facilitating phagocyte engulfment. Certain complement proteins induce inflammation that attracts immune cells to the site of infection. Cell lysis involves the destruction of pathogens through the formation of a...
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Cell adhesion is  an essential aspect of multicellularity. While stable cell interactions usually occur between cells of the same type, transient cell interactions occur between cells of different tissue types, such as between neutrophils and endothelial cells. Selectins are one class of cell adhesion molecules (CAMs) that bind carbohydrate ligands to form transient cell adhesion. They are rod-like proteins with a long extracellular part of variable length ending with the lectin domain,...
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Antibodies, or immunoglobulins, are critical players in the immune system's arsenal against invading pathogens. Produced by B cells and plasma cells, their primary role is to detect and bind to specific antigens, molecules found on the surface of pathogens like bacteria or viruses. Beyond antigen recognition, antibodies perform several vital functions that contribute to immune defense.
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Bispecific Complement Engagers for Targeted Complement Activation.

Dennis V Pedersen1, Heidi Gytz1, Mikael B L Winkler1

  • 1Department of Molecular Biology and Genetics, Center for Structural Biology, Aarhus University, Aarhus C, Denmark.

Journal of Immunology (Baltimore, Md. : 1950)
|June 23, 2023
PubMed
Summary
This summary is machine-generated.

Bispecific antibodies can activate the complement system independently of antibody Fc regions, offering a potent new immunotherapy platform. These novel antibodies demonstrate superior tumor cell killing compared to existing treatments.

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Area of Science:

  • Immunology
  • Biochemistry
  • Oncology

Background:

  • Complement system activation is crucial for antibody effector functions but typically requires multivalent Fc interactions.
  • Efficient complement activation by antibodies is limited to specific subsets due to these Fc-dependent requirements.

Purpose of the Study:

  • To investigate the potential of Fc-independent complement activation using modular bispecific single-domain antibodies.
  • To evaluate the efficacy of these bispecific antibodies in activating complement and inducing tumor cell cytotoxicity.

Main Methods:

  • Design and construction of modular bispecific single-domain antibodies targeting C1q and tumor antigens.
  • Assessment of complement-dependent cytotoxicity against human tumor cell lines expressing target antigens.
  • Comparative analysis with clinically approved antibodies.

Main Results:

  • Bispecific antibodies potently activated the complement system via Fc-independent C1q recruitment.
  • These antibodies exhibited superior complement-dependent cytotoxicity against hematological and solid tumor cell lines.
  • Efficacy was dependent on the C1q binding epitope, highlighting the importance of spatial orientation.

Conclusions:

  • Fc-independent complement activation is achievable with modular bispecific antibodies, offering a novel immunotherapy strategy.
  • This approach overcomes limitations of traditional antibody-mediated complement activation.
  • The modular design allows for versatile targeting, providing a promising platform for cancer immunotherapy development.