Sartorius #2 eBook - 2019 - 10

Importance of mAb Discovery and Development in Immunotherapy

"We do not use a standard platform approach for our bispecific programs," Jäkel
continues, suggesting that by focusing on GlycoTargets, the company has positioned
itself to screen several construct formats for each bispecific product idea. "We can
produce classical IgGs but also bispecific formats in our GlycoExpress system," she
asserts. "We can test different glycosylation variants for identification of a lead
candidate with highest antitumor efficacy."
Although Glycotope is not exclusively focusing on the bsAb market, Jäkel suggests
that there are many possible advantages to targeting two epitopes over monospecific
antibodies, including increased specificity and/or avidity, increased inhibition of tumor
growth, enhanced local tumor cell killing, and blockade of immune checkpoint inhibitors.
Beyond bispecifics
In immuno-oncology, a well-trod path is the redirection of tumor T cells. A lesswell-traveled path is being explored by Invenra, which seeks to activate functional
processes that require a novel mechanism of action through bispecific and higherorder antibody binding.
"A good example is agonist antibodies for the tumor necrosis factor [TNF] receptor
superfamily," says Bonnie Hammer, PhD, vice president of biologic development at
Invenra. "The ligands for that family are trimeric. To get good activity, you need at
least three receptors coming together, but it is even better if you have even
higher-order clustering."
Antibodies that drive this type of receptor clustering are the focus of Invenra's
ARCHER (Agonistic Receptor Clustering by High-order Exogenous Rearrangement)
technology. One of the receptors in the TNF superfamily, OX-40, is the target of
an Invenra bsAb in lead selection.

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To engage the higher-order clustering, Invenra used its B-Body multispecific antibody
development platform to produce a bispecific with a two by one (2 × 1) format. "The
bispecific has three Fab domains," Hammer notes. "But two Fab domains bind to one
epitope, and the other Fab domain binds to a different epitope."
"Traditional monoclonal antibodies for OX-40 have suffered in the clinic," Hammer
says, pointing out that they are dependent on having Fc engagement to provide the
secondary crosslinking needed for activity. In contrast, she continues, Invenra's OX-40
agonist has allowed the company "to achieve activity in the absence of any additional
crosslinking by targeting multiple epitopes." Although the OX-40 agonist has yet to see
the clinic, Hammer suggests that the agonist "will provide higher activity than has been
previously seen with monospecific antibodies."
A bacteriophage library that consists of wholly human Fab fragments and that matches
the natural diversity found in the human repertoire can provide the starting point for
selecting Fabs of interest used in Invenra's B-Body platform, Hammer says. A domainsubstitution strategy with a few orthogonal chain mutations allows for highly specific
light chain-heavy chain pairing and enables high-throughput production and purification of bispecific and multispecific antibodies.
"We found that you can predict some things [during antibody design]," she reports, "but
a lot of it is through empirical testing. The affinities for the antibodies, the geometry,
and the epitopes that you're hitting matter." One other group of multispecific antibodies in Invenra's pipeline consists of discovery candidates that create higher specificity
through the targeting of more than one antigen. "These candidates are the bispecific
antibodies we call the SNIPERsTM," says Hammer. Currently a regulatory T cell-depleting
SNIPER molecule is in lead selection. n
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Sartorius #2 eBook - 2019

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