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Expression liabilities in a four-chain bispecific molecule.

Cai Guo1, Fuyi Chen1, Qiang Xiao1

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Production of multispecific antibodies faces challenges with chain mispairing. This study identified secretion-impaired light chains and promiscuous heavy chains as causes for low product quality in hetero-IgG production.

Keywords:
CHOPbalanced chain expressionintrachain disulfide bondmultichain antibodysecretion capacity

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Area of Science:

  • Biopharmaceutical development
  • Protein engineering
  • Molecular biology

Background:

  • Multispecific antibodies are crucial biotherapeutics with diverse mechanisms of action.
  • Producing correctly paired asymmetric multispecific antibodies presents significant manufacturing challenges.
  • Chain mispairing is a common impurity affecting product quality and yield.

Purpose of the Study:

  • To investigate the causes and consequences of chain mispairing in a difficult-to-express multispecific hetero-IgG.
  • To identify molecular and cellular factors contributing to low product quality.
  • To suggest strategies for improving the production of correctly paired multispecific antibodies.

Main Methods:

  • Transient expression of individual and paired polypeptide chains in mammalian hosts.
  • Analysis of protein secretion competence, cell growth, and endoplasmic reticulum stress markers (CHOP).
  • Investigation of intrachain disulfide bond formation and Russell body induction.

Main Results:

  • A specific light chain (LC) exhibited impaired secretion when expressed alone or with a noncognate heavy chain (HC).
  • Overexpression of the secretion-impaired LC led to reduced cell growth, ER stress, and CHOP induction.
  • The impaired LC formed monomers with incomplete disulfide bonds, and Russell bodies formed upon co-expression with the cognate HC.
  • One heavy chain (HC) demonstrated promiscuous pairing with noncognate light chains.

Conclusions:

  • Identified secretion incompetence of a specific LC and promiscuous pairing of an HC as key drivers of low product quality.
  • Elucidated the molecular and cellular mechanisms underlying chain mispairing impurities.
  • Provided insights for developing mitigation strategies to enhance the production efficiency of correctly paired multispecific antibodies.