Nešić, D., Zhang, Y., Spasic, A., Li, J., Provasi, D., Filizola, M., Walz, T., Coller, B.S. Cryo-Electron Microscopy Structure of the αIIbβ3-Abciximab Complex. Arteriosclerosis Thrombosis Vasc Biology 40, 624–637 (2020). https://doi.org/10.1161/atvbaha.119.313671.

Abstract

Abciximab is one of the first FDA approved chimeric antigen-binding fragments that targets the platelet integrin αIIbβ3 receptor inhibiting platelet aggregation. As a chimeric mAb, abciximab was engineered by combining the variable region of a murine mAb and the constant domains of a human IgG. Since approved in 1993, more than 5 million patients have been treated with abciximab. Although abciximab’s binding to the platelet integrin αIIbβ3 receptor has been biochemically studied, the exact binding site between the two molecules was never elucidated due to lack of both abciximab sequence information and sufficiently advanced techniques. 

The gap remained until recently researchers from the Coller Lab at The Rockefeller University used cryo-electron microscopy (cryo-EM) to solve the structure of abciximab-αIIbβ3 complex at 2.8 Å resolution. As part of the structure determination effort, the full-length amino acid sequence of abciximab was determined by Rapid Novor’s REmAb de novo sequencing service. The 3D structure allows people for the first time to precisely visualize the αIIbβ3-abciximab binding interface, and identify the binding residues on all 3 complementarity-determining regions of abciximab as well as the specificity-determining loop of αIIbβ3. The study further provides the molecular mechanism of how abciximab prevents ligands from access to αIIbβ3, thus inhibiting platelet aggregation.    

The lag of over 20 years between the approval of abciximab and its structure determination has reflected a common deficiency in mAb therapeutics development – scarcity of structural knowledge. Among over 175,000 solved structures stored in the Protein Data Bank (PDB), the number of structures for therapeutic mAbs is very low (less than 100), and there is no known structural information for bispecific immunotherapeutics

Structural information of therapeutic antibody candidates and binding targets are of great importance in drug design, lead selection, and optimization. Structures of approved and marketed drugs, including their intermediate candidates, can be useful for many applications, such as drug repurposing and biosimilar development. Finally, functional characterization and structural knowledge of antibodies solely used for research may also find their potential for medical applications. 

De novo protein sequencing can be applied here to obtain sequence information of any antibody/protein sequence throughout drug development. Well known and functionally validated antibodies against a variety of antigens may also be de novo sequenced. Structural information is then accessible for both the intended drugs and drug-target complexes, which is central to the design and production of the next generation of biologics and biosimilars.

Graphical Abstract

Graphical representation of the orthogonal methods used to solve the structure of the abciximab-αIIbβ3 complex, providing insight into the mechanistic binding of the FDA-approved chimeric mAb.

Key Takeaways

  • The Coller Lab applied orthogonal structural approaches, including de novo protein sequencing and cryo-electron microscopy, to characterize the structure of the marketed mAb therapeutic abciximab bound to the target receptor αIIbβ3.
  • Structural characterization techniques can fill in the information gap that is abundantly present for many of the therapeutic antibody candidates and marketed immunotherapeutics.

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Through next generation protein sequencing, Rapid Novor enables reliable discovery and development of novel reagents, diagnostics, and therapeutics. Thanks to our Next Generation Protein Sequencing and antibody discovery services, researchers have furthered thousands of projects, patented antibody therapeutics, and developed the first recombinant polyclonal antibody diagnostics.

Talk to Our Scientists.

We Have Sequenced 6000+ Antibodies and We Are Eager to Help You.

Through next generation protein sequencing, Rapid Novor enables timely and reliable discovery and development of novel reagents, diagnostics, and therapeutics. Thanks to our Next Generation Protein Sequencing and antibody discovery services, researchers have furthered thousands of projects, patented antibody therapeutics, and ran the first recombinant polyclonal antibody diagnostics

Talk to our scientists. We have sequenced over 6000 antibodies and we are eager to help you.