Sartorius #2 eBook - 2019 - 6

Importance of mAb Discovery and Development in Immunotherapy

Even while monospecific antibody-based checkpoint inhibition therapies and CAR
T-cell therapies continue to be improved, bispecific and multispecific antibodies are
shaping up as cancer immunotherapy options that may provide significant advantages.
At present, companies such as Amunix Operating, Invenra, Glycotope, and Xencor are
working independently and in collaboration with larger pharmaceutical companies,
such as Novartis, Daiichi Sankyo, and Roche, to bring bispecific and higher-order
antibodies into the cancer immunotherapy market. Fundamentally, their engineered
expression platforms focus on streamlining novel antibody development, reducing the
risk factors to patients, and optimizing tumor destruction.

Increasing Selectivity
bsAbs emerged with the technologies developed by two pioneering companies Amgen
and MacroGenics. Amgen introduced the BiTE platform; MacroGenics, the DART
platform. Despite the availability of such platforms, it can still be a challenge to
produce bsAbs that incorporate an Fc domain, suggests John Desjarlais, PhD, senior
vice president of research and CSO at Xencor. "If you don't have an Fc domain," he
says, "you have a very short half-life," necessitating low and frequent injections or
continuous infusion in patients.
Xencor's solution was to build a robust and GMP-scalable bispecific platform that
includes an engineered Fc domain for the antibody, ensuring that antibodies produced
with this platform would have a longer half-life in vivo. Xencor's XmAb Fc platform
increases this efficiency of heterodimer Fc formation to 95% out of the gate.
"If I want to make a heterodimeric Fc domain, one that is different on either side," he
says of a traditional process, "I'm going to get a mixture of 50% of the heterodimer,
and 25% of the different homodimers by comparison."
To improve efficiency yet further, Xencor has engineered an additional feature in
the Fc domain. "We perturb the isoelectric point on either side of the Fc heterodimer
through substitutions in the Ch3 domains," Desjarlais details. "The idea behind that
was, we would have an ability to very easily separate out the small amount of
contaminating homodimers just by using ion exchange chromatography."

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Sartorius #2 eBook - 2019

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