Sartorius #2 eBook - 2019 - 14

Importance of mAb Discovery and Development in Immunotherapy

binds to CD19 highly expressed on the surface of cells of B-lineage origin and CD3
expressed on the surface of T cells, forming a "synapse" between the cells, according to
the company's website. Once the synapse is formed, blinatumumab leads to upregulation of cell-adhesion molecules and the production of cytolytic proteins that destroy
the tumor cells.
Coping with Production Challenges
Despite great advances in antibody design, bispecifics pose production challenges
distinct from developing and manufacturing monoclonals, as they require two different
heavy chains, and two different light chains.
"Proper assembly of heavy and light chains has been one of the biggest technical
hurdles in developing therapeutic bispecifics," comments Paul Carter, Ph.D., senior
director and senior staff scientist, antibody engineering, Genentech. "Co-expression of
two different antibodies in the same cell can lead to up to nine different chain pairings
in addition to the desired bispecifics.
"At Genentech, we've invented a way to modify the two heavy chains of a given
bispecific so that they fit together only in the desired manner. This technology, which
exemplifies the knobs-into-holes approach, proved a critical technical innovation that
helped make the large-scale manufacturing of bispecifics possible. It is now possible
to generate bispecific antibodies in sufficient quality and purity for therapeutic use in
clinical trials. We are also seeing production meet demand following the recent FDA
approvals of new types of bispecifics."

human IgG1, IgG2, and IgG4, as well as reverse chimeric IgG2a). Additionally, these
scientists demonstrated that their designs can be used for efficient single-cell production
of bsIgG in stable CHO cell lines, concluding that these single-cell-bispecific IgG designs
may be broadly applicable for applications in biotechnology.
Dr. Carter further noted that Genentech is currently evaluating an investigational
bslgG, mosunetuzumab, in a Phase I/Ib dose-escalation study. In this study,
mosunetuzumab is being administered as a single agent and in combination with
atezolizumab in participants with relapsed or refractory B-cell non-Hodgkin
lymphoma and chronic lymphocytic leukemia.
Mosunetuzumab was designed to engage T cells and redirect their cytotoxic activity
to a component of the T-cell receptor complex, and to CD20, a B-cell surface protein
expressed in a majority of B-cell malignancies.
Bassil Dahiyat, Ph.D., Xencor's president and CEO, spoke with GEN about how the
company's XmAb Fc platform may overcome specific challenges in bsAb production and
enable construction of more fully functional antibodies. "The ability to bind two targets
creates a vastly greater number of new therapeutics," he says. "By engaging two targets
you can open a world of possibilities.
"The Fc domain, one-third of an antibody's structure, endows antibodies with properties such as long half-life, high stability, and ease of purification. The big innovation
in the last few years has been that people figured out how to make bispecifics with Fc
domains. Xencor's bispecific Fc domains maintain full-length antibody properties and
can be made and purified with standard antibody production methods."

Besides enabling the heterodimerization of heavy chains, the knobs-into-holes technology can be used to achieve the correct association of the light chains and their
cognate heavy chains by exchange of heavy-chain and light-chain domains within the
antigen binding fragment (Fab) of one half of the bsAb.

"We used structure-based design to try to get at the property we want, in this case
heterodimer structure in the Fc domain, to enable bispecific antibodies with Fcs,"
he continues. "We characterized the molecules we got by screening for specific
characteristics like receptor binding and stability in our design.

Genentech scientists recently reported the development of novel orthogonal Fab designs
and demonstrated that they can be used together with knobs-into-holes mutations
for efficient single-cell production of bsIgG of different isotypes and species (including

"The success of bispecifics will depend on how simple they are to manufacture. That
was a major design goal. We wanted to duplicate existing processes for manufacturing
monoclonal antibodies, and we succeeded in doing that."

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Sartorius #2 eBook - 2019

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