4UB0

New design for monovalent bispecific IgG through cysteine engineering of the CH1-CL interface


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.232 
  • R-Value Observed: 0.233 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Improving target cell specificity using a novel monovalent bispecific IgG design.

Mazor, Y.Oganesyan, V.Yang, C.Hansen, A.Wang, J.Liu, H.Sachsenmeier, K.Carlson, M.Gadre, D.V.Borrok, M.J.Yu, X.Q.Dall'Acqua, W.Wu, H.Chowdhury, P.S.

(2015) MAbs 7: 377-389

  • DOI: https://doi.org/10.1080/19420862.2015.1007816
  • Primary Citation of Related Structures:  
    4UB0

  • PubMed Abstract: 

    Monovalent bispecific IgGs cater to a distinct set of mechanisms of action but are difficult to engineer and manufacture because of complexities associated with correct heavy and light chain pairing. We have created a novel design, "DuetMab," for efficient production of these molecules. The platform uses knobs-into-holes (KIH) technology for heterodimerization of 2 distinct heavy chains and increases the efficiency of cognate heavy and light chain pairing by replacing the native disulfide bond in one of the CH1-CL interfaces with an engineered disulfide bond. Using two pairs of antibodies, cetuximab (anti-EGFR) and trastuzumab (anti-HER2), and anti-CD40 and anti-CD70 antibodies, we demonstrate that DuetMab antibodies can be produced in a highly purified and active form, and show for the first time that monovalent bispecific IgGs can concurrently bind both antigens on the same cell. This last property compensates for the loss of avidity brought about by monovalency and improves selectivity toward the target cell.


  • Organizational Affiliation

    a Department of Antibody Discovery and Protein Engineering ; MedImmune ; Gaithersburg , MD USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
IgG1, heavy chainA [auth H]220Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
IgG1, light chainB [auth L]214Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.232 
  • R-Value Observed: 0.233 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 126.154α = 90
b = 64.045β = 129.09
c = 82.395γ = 90
Software Package:
Software NamePurpose
REFMACrefinement

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-07-15
    Type: Initial release
  • Version 1.1: 2023-12-27
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description, Source and taxonomy