Antibody fusion proteins with human ribonucleases 1 to 8

Xenia Wezler1, Stefan Dübel1, Thomas Schirrmann2

  • 1Technische Universität Braunschweig, Institute of Biochemistry, Biotechnology and Bioinformatics, 38106 Braunschweig, Germany.

Human Antibodies
|April 26, 2018
PubMed

Insights

This study explored human ribonuclease (RNase) A family members as cancer-fighting immunoRNases. Some immunoRNases showed potent, antigen-specific tumor growth inhibition, independent of their RNase activity or inhibitor sensitivity.

Area of Science:

  • Biochemistry
  • Immunology
  • Oncology

Background:

  • ImmunoRNases leverage antibody-mediated tumor targeting and cytotoxic ribonuclease (RNase) activity.
  • Human RNase A superfamily members are potential candidates for immunoRNase development.

Purpose of the Study:

  • To investigate all catalytic active human RNase A family members (1-8) as effector components in antibody fusion proteins.
  • To evaluate the CD30-specific binding, ribonucleolytic activity, and tumor growth inhibition of novel immunoRNases.

Main Methods:

  • Construction of immunoRNase fusion proteins using a CD30-specific antibody (SH313-B5).
  • Production of fully human immunoRNases in mammalian cells.
  • Assessment of enzyme activity in the presence of pancreatic RNase inhibitor (RI).
  • Evaluation of antigen-specific anti-tumor activity and tumor growth inhibition in vitro.

Main Results:

  • All generated immunoRNases exhibited CD30-specific binding and ribonucleolytic activity.
  • ImmunoRNases 1 and 2 displayed resistance to RNase inhibitor (RI), while others showed varying sensitivity.
  • Antibody fusion or dimerization did not significantly alter RNase activity or RI sensitivity.
  • ImmunoRNases 3 and 5 demonstrated potent, antigen-specific tumor growth inhibition at nanomolar concentrations.

Conclusions:

  • Human RNase A family members can be effectively engineered into functional immunoRNases.
  • Anti-tumor efficacy of immunoRNases is antigen-specific and not directly correlated with ribonucleolytic activity or RI sensitivity.
  • Certain immunoRNases show promising therapeutic potential for CD30-positive malignancies.

Related Concept Videos

Nuclear Fusion02:45

Nuclear Fusion

The process of converting very light nuclei into heavier nuclei is also accompanied by the conversion of mass into large amounts of energy, a process called fusion. The principal source of energy in the sun is a net fusion reaction in which four hydrogen nuclei fuse and ultimately produce one helium nucleus and two positrons.
A helium nucleus has a mass that is 0.7% less than that of four hydrogen nuclei; this lost mass is converted into energy during the fusion. This reaction produces about...
33.9K
Tagging and Fusion Proteins01:24

Tagging and Fusion Proteins

Proteins are involved in several cellular processes and biochemical reactions. Analyzing a specific protein of interest requires it to be isolated from the other proteins in the cell. This is achieved by overexpressing the specific gene in a suitable host to produce large quantities of the target protein. A tag or label is recombined with the gene to produce a fusion protein containing the target protein and the tag. The tags on these fusion proteins can then be used for easy detection and...
8.5K
Antibody Structure01:10

Antibody Structure

Overview
Antibodies, also known as immunoglobulins (Ig), are essential players of the adaptive immune system. These antigen-binding proteins are produced by B cells and make up 20 percent of the total blood plasma by weight. In mammals, antibodies fall into five different classes, which each elicits a different biological response upon antigen binding.
The Y-Shaped Structure of Antibodies Consists of Four Polypeptide Chains
Antibodies consist of four polypeptide chains: two identical heavy...
65.7K
SNAREs and Membrane Fusion01:43

SNAREs and Membrane Fusion

Once a transport vesicle has recognized its target organelle, the vesicular membrane needs to fuse with the target membrane to unload the cargo. Transmembrane proteins called SNAREs present on organelle membranes and their vesicles, mediate vesicle fusion.
SNAREs exist in pairs that symmetrically interact and catalyze the fusion of the lipid bilayers in vesicle and target organelle. v-SNARE in the vesicle membrane are single polypeptide chains that bind to a complementary t-SNARE, composed of 2...
12.9K
Role of Proteins in the Human Body01:28

Role of Proteins in the Human Body

Proteins are the building block of life. They are also  the most abundant macromolecules with as many diverse roles in the body. They are part of many structural components that provide unique shapes and structures to animal cells, tissues, and organs. In addition, they also act as biological catalysts and carry out several anabolic and catabolic reactions. Notably, some proteins are chemical messengers and regulate many critical processes, such as metabolism, growth, and development. They...
6.6K
Antibody Actions01:26

Antibody Actions

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.
Neutralization
Antibodies can bind to pathogens, preventing them from infecting host cells. This process...
2.9K