Origene_Jan2021_ProperAntibodyDesignKeeps - 20

Bispecific, Multispecific Antibodies Grapple with Cancer
half-life, " necessitating low and frequent injections

Dual-targeting antibodies may promote less toxicity

or continuous infusion in patients.

by more selectively targeting the tumor reactive T

Xencor's solution was to build a robust and

cells. " The idea is to turn off the brakes, " he explains,

GMP-scalable bispecific platform that includes an

" and the more brakes you can hit at the same time,

engineered Fc domain for the antibody, ensuring

the more you can activate those tumor T cells. "

that antibodies produced with this platform would

In addition to checkpoint inhibitors, Xencor has

have a longer half-life in vivo. Xencor's XmAb Fc

been successful in establishing two Phase I trials

platform increases this efficiency of heterodimer Fc

in collaboration with Novartis involving T-cell-en-

formation to 95% out of the gate.

gaging bsAbs; one that has an AML indication and

" If I want to make a heterodimeric Fc domain,

binds to CD123 on AML blasts and CD3 on T cells,

one that is different on either side, " he says of a

and a second that binds to CD20 on malignant

traditional process, " I'm going to get a mixture of

B cells and CD3 on T cells. The company has a

50% of the heterodimer, and 25% of the different

third wholly owned bsAb that binds CD3/SSTR2

homodimers by comparison. "

(somatostatin receptor 2). Currently in Phase I trials,

To improve efficiency yet further, Xencor has
engineered an additional feature in the Fc domain.
" We perturb the isoelectric point on either side of

this bsAb is being explored with dose escalation in
neuroendocrine tumors.
" CD3 bispecifics would be considered direct

the Fc heterodimer through substitutions in the Ch3

competitors to CAR-T, " asserts Desjarlais. CAR T-cell

domains, " Desjarlais details. " The idea behind that

therapies require weeks of preparation including

was, we would have an ability to very easily separate

cellular extraction from a patient, engineering in

out the small amount of contaminating homodimers

vitro, culturing, speculative dosing, and continued

just by using ion exchange chromatography. "

growth in vivo. In contrast, Desjarlais points out,

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

" 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

as nivolumab (Opdivo; anti-PD1) and ipilimumab

Amunix, affirms that the challenge of the CAR T-cell

(Yervoy; anti-CTLA-4) have been used in combination

therapies is that they must be individually created

to improve antitumor activity, but this approach, says

for each patient. " Another challenge, " he says, " is that

Desjarlais, comes at the cost of increased toxicity.

you are injecting live cells into a patient. So, it is very

20 |

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