Origene_Jan2021_ProperAntibodyDesignKeeps - 24

Bispecific, Multispecific Antibodies Grapple with Cancer
three receptors coming together, but it is even

that the agonist " will provide higher activity than has

better if you have even higher-order clustering. "

been previously seen with monospecific antibodies. "

Antibodies that drive this type of receptor clus-

A bacteriophage library that consists of wholly

tering are the focus of Invenra's ARCHER (Agonistic

human Fab fragments and that matches the

Receptor Clustering by High-order Exogenous

natural diversity found in the human repertoire

Rearrangement) technology. One of the receptors

can provide the starting point for selecting Fabs of

in the TNF superfamily, OX-40, is the target of an

interest used in Invenra's B-Body platform, Hammer

Invenra bsAb in lead selection.

says. A domain-substitution strategy with a few

To engage the higher-order clustering, Invenra

orthogonal chain mutations allows for highly

used its B-Body multispecific antibody development

specific light chain-heavy chain pairing and enables

platform to produce a bispecific with a two by

high-throughput production and purification of

one (2 × 1) format. " The bispecific has three Fab

bispecific and multispecific antibodies.

domains, " Hammer notes. " But two Fab domains

" We found that you can predict some things

bind to one epitope, and the other Fab domain

[during antibody design], " she reports, " but a lot

binds to a different epitope. "

of it is through empirical testing. The affinities for

" Traditional monoclonal antibodies for OX-40

the antibodies, the geometry, and the epitopes

have suffered in the clinic, " Hammer says, pointing

that you're hitting matter. " One other group of multi-

out that they are dependent on having Fc engage-

specific antibodies in Invenra's pipeline consists of

ment to provide the secondary crosslinking needed

discovery candidates that create higher specificity

for activity. In contrast, she continues, Invenra's

through the targeting of more than one antigen.

OX-40 agonist has allowed the company " to achieve

" These candidates are the bispecific antibodies

activity in the absence of any additional crosslinking

we call the SNIPERsTM, " says Hammer. Currently a

by targeting multiple epitopes. " Although the OX-40

regulatory T cell-depleting SNIPER molecule is in

agonist has yet to see the clinic, Hammer suggests

lead selection. ●

24 |

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