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Engineering therapeutic bispecific antibodies using CrossMab technology.

Christian Klein1, Wolfgang Schaefer2, Joerg T Regula2

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CrossMab technology enables efficient bispecific antibody production by ensuring correct chain association. This versatile platform supports various formats, with multiple bispecific antibodies advancing in clinical development.

Keywords:
AntibodyBispecificCrossMabDomain crossoverT cell bispecific

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Area of Science:

  • Biotechnology
  • Immunology
  • Protein Engineering

Background:

  • Bispecific antibodies offer novel therapeutic applications beyond conventional IgG antibodies.
  • Engineering IgG-based bispecific antibodies faces challenges in correct heavy and light chain association and assembly yield.
  • Existing methods for bispecific antibody generation require improvement for large-scale therapeutic production.

Purpose of the Study:

  • To introduce and review the CrossMab technology for engineering bispecific antibodies.
  • To highlight the versatility of CrossMab technology in generating diverse bispecific antibody formats.
  • To summarize the progress and therapeutic applications of CrossMab-based bispecific antibodies.

Main Methods:

  • Development of the CrossMab technology, enforcing correct light chain association via domain crossover in the Fab region.
  • Application of CrossMab technology in combination with Fc-heterodimerization approaches (e.g., knob-into-hole).
  • Adaptation of CrossMab technology for large-scale production of therapeutic bispecific antibodies.

Main Results:

  • CrossMab technology enables the generation of asymmetric heterodimeric monovalent (1+1) and bispecific (2+1) antibodies.
  • CrossMab technology facilitates the creation of tetravalent symmetric (2+2) bispecific antibodies (Tandem-Fab based IgG).
  • At least eight bispecific antibodies utilizing CrossMab technology have entered clinical trials, with more in late preclinical stages.

Conclusions:

  • CrossMab technology provides a robust solution for the correct assembly and high-yield production of diverse bispecific antibody formats.
  • The successful clinical progression of multiple CrossMab-based antibodies underscores the technology's therapeutic potential.
  • CrossMab technology represents a significant advancement in the engineering and application of bispecific antibodies for therapeutic use.