An ultra-stable cytoplasmic antibody engineered for in vivo applications

Hiroyuki Kabayama (), Makoto Takeuchi, Naoko Tokushige, Shin-ichi Muramatsu, Miyuki Kabayama, Mitsunori Fukuda, Yoshiyuki Yamada and Katsuhiko Mikoshiba ()
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Hiroyuki Kabayama: Institute of Physical and Chemical Research
Makoto Takeuchi: Institute of Physical and Chemical Research
Naoko Tokushige: Institute of Physical and Chemical Research
Shin-ichi Muramatsu: Jichi Medical University
Miyuki Kabayama: Nippon Veterinary and Life Science University
Mitsunori Fukuda: Tohoku University
Yoshiyuki Yamada: Institute of Physical and Chemical Research
Katsuhiko Mikoshiba: Institute of Physical and Chemical Research

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: Abstract Targeting cytoplasmic protein–protein interactions with antibodies remains technically challenging, since antibodies expressed in the cytosol frequently form insoluble aggregates. Existing engineering methods are based on the notion that the estimated net charge at pH 7.4 affects stability; as such, they are unable to overcome this problem. Herein, we report a versatile method for engineering an ultra-stable cytoplasmic antibody (STAND), with a strong estimated net negative charge at pH 6.6, by fusing peptide tags with a highly negative charge and a low isoelectric point. Without the need for complicated amino acid substitutions, we convert aggregation-prone antibodies to STANDs that are useful for inhibiting in vivo transmitter release, modulating animal behaviour, and inhibiting in vivo cancer proliferation driven by mutated Kras—long recognised as an “undruggable” oncogenic protein. The STAND method shows promise for targeting endogenous cytoplasmic proteins in basic biology and for developing future disease treatments.

Date: 2020
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DOI: 10.1038/s41467-019-13654-9

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