Sartorius #2 eBook - 2019 - 18

Importance of mAb Discovery and Development in Immunotherapy

"This is why early efforts to produce IL-15 did not generate satisfactory yields in
mammalian cells, because people were only producing half the protein, which was
destroyed intracellularly," explains Dr. Pavlakis. After scaling up heterodimeric IL-15
production, investigators in Dr. Pavlakis' lab revealed that the cytokine delays tumors in
mice. "On the basis of this work, we initiated a collaboration with Thomas A. Waldmann,
M.D. [co-chief, lymphoid malignancies branch, NCI], and Kevin C. Conlon, M.D. [associate
research physician, lymphoid malignances branch, NCI], and heterodimeric IL-15 is
now in clinical trials for cancer immunotherapy," says Dr. Pavlakis. Clinical trials with
heterodimeric IL-15 are now being continued by Novartis.
This work illustrates the critical role of interdisciplinarity in advancing basic research
and in translating the findings to clinical applications. "We faced a lot of skepticism.
People did not believe that a noncovalently linked heterodimer is stable, and we had
a difficult time convincing the scientific community that these complexes could be
developed as a drug," recalls Dr. Pavlakis. The work by Dr. Pavlakis and colleagues also
catalyzed a recent correction in immunology texts, where the prevailing idea until
recently has been that free IL-15 binds to the IL-15 receptor alpha to initiate signaling.
"There is no IL-15 receptor alpha. This protein does not have a receptor function, but it
is the misnamed other half of the heterodimeric IL-15 cytokine, and this correction also
led to practical applications in clinical development," states Dr. Pavlakis.
"When we linked IL-2 to the IL-2 receptor beta, we had in mind many problems that
scientists encountered in the past when they were trying to activate immune cells,"
says Youssef Jounaidi, Ph.D., instructor of anesthesia at Harvard Medical School. The
ability of IL-2 to enhance the antitumor and antiviral effects of NK cells and T cells
was reported years ago, and clinical trials subsequently exploited this finding. "But the
excitement was short-lived, and one of the reasons was that high-dose IL-2 causes
several side effects, such as pulmonary edema," explains Dr. Jounaidi.
IL-2 signaling is mediated through a multisubunit receptor complex that contains alpha,
beta, and gamma subunits. IL-2 binds with low affinity to the IL-2 receptor alpha, and
with intermediate affinity to the IL-2 receptor beta complexed with the gamma chain.

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NK cells are relatively insensitive to low IL-2 levels. However, regulatory T cells have high
receptor-alpha levels and outcompete other immune cells for IL-2, which opens another
challenge in using IL-2 to modulate the immune response.
Arming Cancer Cells with IL-2
A new approach developed by Dr. Jounaidi and colleagues involves tethering IL-2 to
the IL-2 receptor beta using a peptide linker. The newly generated fusion protein was
used to genetically modify NK cells to induce IL-2 expression. Activated immune cells
expressing this construct expanded indefinitely in a feedback loop, without the need for
exogenous IL-2. In vitro, immune cells expressing this chimeric protein showed cytotoxicity comparable to or higher than wild-type IL-2. The construct also led to better
anticancer effects and superior survival in mouse models. "The idea of arming tumor
cells with IL-2 to survive in the tumor microenvironment is not new. Investigators just
did not have the means to do it efficiently, and we believe that our chimera will help
immune cells better survive in the highly immunosuppressive tumor microenvironment,"
states Dr. Jounaidi.
A small subset of NK cells are able to lyse multiple target cells in a consecutive fashion,
elicit faster and stronger lytic responses, and replenish their cytokine stores. These
cells have become known as serial killers. "NK cells that expressed our chimeric protein
showed an increase in lytic enzymes upon contact with cancer cells," reports Dr.
Jounaidi.
The chimeric construct also conferred resilience to TGF-beta1, which is secreted by
cancer-associated fibroblasts and other cells in the tumor microenvironment and
inhibits the anticancer responses of immune cells. "One strategy to fight cancer is to
arm cancer-fighting immune cells with an additional mechanism to resist immunosuppression in the tumor microenvironment, and tethering IL-2 to its receptor beta would
solve this problem," asserts Dr. Jounaidi.

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Sartorius #2 eBook - 2019

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