BioCentury article: CD38 Hat Trick

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Tusk Therapeutics Ltd. thinks its anti-CD38 mAb could be best in class for solid tumors because it not only kills cancer cells and inhibits immunosuppressive cells, as its competitors do, but it also directly activates effector T cells.

The CD38 space initially gained prominence based on the speedy development and commercial success of Genmab A/S and Johnson & Johnson’s Darzalex daratumumab in multiple myeloma (MM).
More recently, the target has drawn interest as a possible checkpoint inhibitor in solid tumors and blood cancers as it is highly expressed on immunosuppressive cells that limit activation of effector T cells.
In a July 2016 study in Blood, J&J showed Darzalex monotherapy increased the number of peripheral versus bone marrow CD8+ T cells in MM patients.

Tusk co-founder and CEO Luc Dochez told BioCentury the biotech discovered CD38’s direct action on effector T cells almost on accident.

After screening for mAbs that kill cancer cells, he said “just out of curiosity” the company tested its leads in a second assay it had designed for a different target. The assay was set up to identify activators of effector T cells. “We picked up on a signal in a couple molecules that was quite impressive,” he said.
Additional studies confirmed Tusk’s lead mAb, which does not yet have a name, activates both CD8+ and CD4+ T cells and works by direct and indirect mechanisms. The indirect mechanism involves killing CD38-expressing immunosuppressive cells in the tumor microenvironment; the direct mechanism is undisclosed.

“The effector T cell responses are consistently higher than with Darzalex,” said Dochez.
At the Society for Immunotherapy of Cancer (SITC) meeting in November, Tusk presented data demonstrating its anti-CD38 mAb induced statistically significantly higher levels of T cell activation than Darzalex in the same in vitro assay, and increased markers of CD8+ T cell activation in non-human primates.

Dochez said Tusk’s mAb targets a different epitope on CD38 than Darzalex, which could explain the compounds’ differential effects on effector T cell activation and proliferation.
Tusk plans to bring the mAb into the clinic for solid tumors in 2H18. J&J, which did not respond to a request for comment, has started multiple Phase I/II trials of Darzalex in combination with PD-1 or PD-L1 inhibitors to treat solid tumors. The pharma has not published data from Darzalex in solid
tumors.

At least two other anti-CD38 mAb programs are in the clinic for MM. Sanofi’s isatuximab is in Phase III and MorphoSys AG’s MOR202 is in Phase II. Dochez said he isn’t aware of any publication that shows either mAb activates effector T cells directly. Sanofi told BioCentury published data show isatuximab targets Tregs in MM. MorphoSys didn’t respond to request to comment.

Tusk’s second program is a mAb against interleukin-2 (IL-2) receptor alpha chain (CD25). Dochez said CD25 was once a hot target in cancer, but was largely abandoned after several programs failed to show clinical benefit. The reason for the failures, he said, was that the molecules did not deplete Tregs in the tumors, despite depleting them from the blood and lymph nodes.

By contrast, he said Tusk’s anti-CD25 mAb can deplete Tregs from the tumor microenvironment. He added that the mAb synergizes with PD-1 blockade and, based on undisclosed modifications the company made to it, will likely prove a good alternative to CTLA-4 inhibitors like Yervoy ipilimumab from Bristol-Myers Squibb Co.

According to Dochez, Tusk’s €30 million ($35.4 million) series A will get both programs into the clinic. He expects the CD25 mAb to start clinical testing in 1H19. The indication is undisclosed.
Over the next six months, the company aims to raise a series B round of undisclosed size to finance both programs through clinical proof of concept. Dochez expects the first efficacy readout from the CD38 program in 2019.

BioCentury on BioBusiness, December 18, 2017, Emerging Company Profile section article, “CD38 Hat Trick” written by Mr.  Stephen Hansen, MPhil, BioCentury Associate Editor


COMPANIES AND INSTITUTIONS MENTIONED

Bristol-Myers Squibb Co. (NYSE:BMY), New York, N.Y.

Genmab A/S (CSE:GEN; Pink:GMXAY), Copenhagen, Denmark

Johnson & Johnson (NYSE:JNJ), New Brunswick, N.J.

MorphoSys AG (Xetra:MOR; Pink:MPSYY), Martinsried, Germany

Sanofi (Euronext:SAN; NYSE:SNY), Paris, France

Tusk Therapeutics Ltd., Stevenage, U.K.


REFERENCES

Arce Vargas, F., et. al. “Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and
synergizes with PD-1 blockade to eradicate established tumors.” Immunity (2017)

Hansen, S.Genmab’s second act.” BioCentury (2017)

Krejcik, J., et. al.Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion,and skews T-cell repertoire in multiple myeloma. Blood (2016)