Sartorius #2 eBook - 2019 - 7

Importance of mAb Discovery and Development in Immunotherapy

Xencor is exploring bsAbs that act as dual checkpoint inhibitors, such as anti-PD-1/
CTLA-4 and CTLA-4/LAG-3. The field has learned that cancer evolves to suppress the
immune system by engaging different pathways meant to protect the body against
autoimmunity.
Single checkpoint blockers on the market such as nivolumab (Opdivo; anti-PD1) and
ipilimumab (Yervoy; anti-CTLA-4) have been used in combination to improve antitumor
activity, but this approach, says Desjarlais, comes at the cost of increased toxicity.
Dual-targeting antibodies may promote less toxicity by more selectively targeting the
tumor reactive T cells. "The idea is to turn off the brakes," he explains, "and the more
brakes you can hit at the same time, the more you can activate those tumor T cells."
In addition to checkpoint inhibitors, Xencor has been successful in establishing two
Phase I trials in collaboration with Novartis involving T-cell-engaging bsAbs; one that
has an AML indication and binds to CD123 on AML blasts and CD3 on T cells, and a
second that binds to CD20 on malignant B cells and CD3 on T cells. The company has
a third wholly owned bsAb that binds CD3/SSTR2 (somatostatin receptor 2). Currently
in Phase I trials, this bsAb is being explored with dose escalation in neuroendocrine
tumors.
"CD3 bispecifics would be considered direct competitors to CAR-T," asserts Desjarlais.
CAR T-cell therapies require weeks of preparation including cellular extraction from a
patient, engineering in vitro, culturing, speculative dosing, and continued growth in
vivo. In contrast, Desjarlais points out, "a bispecific is something in a vial that you have
in the pharmacy."
"With a bispecific," he emphasizes, "you know exactly what you're putting in.".

T-cell engagers
Volker Schellenberger, PhD, president and CEO of Amunix, affirms that the challenge
of the CAR T-cell therapies is that they must be individually created for each patient.
"Another challenge," he says, "is that you are injecting live cells into a patient. So, it is
very difficult to control what happens to them. They can even multiply in that person."

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Sartorius #2 eBook - 2019

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