Sartorius #2 eBook - 2019 - 17

Importance of mAb Discovery and Development in Immunotherapy

"The overall goal, by making these bifunctional fusion proteins, was to hopefully make
the immune system a little bit stronger than the tumor cells," points out Dr. Wei.
NK cells are critical in monitoring tumor development because of their multiple
surface receptors, some inhibitory and others activatory. Whether a cell will be
activated or inhibited depends on the balance between the two types of signals. The
NKG2D receptor and its ligands, NKG2DLs, are critical for cancer immune surveillance,
and the generation of multifunctional fusion proteins based on these interactions has
become a very active research area.
While NK cells are important in the early stages of immune surveillance, the challenges are when a tumor cell escapes this process, accumulates more mutations, and
stops producing the stress proteins. Dr. Wei's lab is currently interested in finding
ways to place several of these bifunctional proteins into cells together to simultaneously engage different cellular pathways. "But it is very challenging to simultaneously
deliver multiple fusion protein gene products into tumor cells," states Dr. Wei.
Heterodimeric IL-15
"The major initial advancement was the realization that IL-15 is a heterodimeric
complex naturally," declares George N. Pavlakis, M.D., Ph.D., chief of the human
retrovirus section, vaccine branch, at the Center for Cancer Research of the National
Cancer Institute (NCI). At that time, members of the IL-12 family, including IL-12,
IL-23, and IL-27, were known to be heterodimeric cytokines linked by disulfide bonds.
"What was not appreciated was that, although in heterodimeric IL-15 the two
subunits are not linked by disulfide bonds, the affinity of those subunits for each
other is so strong that it brings it pretty close to a disulfide bond covalently linked
molecule," says Dr. Pavlakis.
The production of stable IL-15 in cells requires the coordinate expression of the two
subunits, IL-15 and IL-15 receptor alpha polypeptides. If the heterodimeric form of
the cytokine is not generated, the individual subunits are to a great extent targeted
for destruction by the cellular quality control systems.
17 |

GENengnews.com

National Cancer Institute researchers led by George N. Pavlakis, M.D., Ph.D., have been
developing heterodimeric IL-15 (hetIL-15) as an immuno-oncologic drug. The images
show the accumulation of granzyme B-positive cytotoxic T cells in lymph node follicles
after hetIL-15 treatment. Staining: CD20+ (B cells, blue); CD3+ (T cells, red); and GrzB+
(T cells, yellow). [Moysi, Petrovas, and Pavlakis, NIH, 2018]

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Sartorius #2 eBook - 2019

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