The expression of CD137 on immune cells has made the protein receptor an attractive target in the development of new cancer immunotherapy drugs. Now, Compass Therapeutics has some early data showing that its CD137 agonist, CTX-471, could work safely in solid tumors.
In a study published in JCI Insight, Compass researchers demonstrated that CTX-471 given alone eliminated tumors in mice without triggering liver toxicity. It also caused some shrinkage of large tumors that had not responded to existing immuno-oncology agents targeting the checkpoints PD-1/L1 and CTLA-4.
Executives of the Cambridge, Massachusetts-based biotech, a 2018 Fierce 15 winner, are so encouraged by the findings they have advanced the antibody drug into phase 1 testing in patients with advanced cancers that have progressed after being treated with PD-1/L1 inhibitors.
CD137, or 4-1BB, is known to be expressed on multiple immune cells, including natural killer (NK) cells, monocytes and activated CD4+ and CD8+ T cells. CD137 agonists have the potential to kill tumor cells by activating cytotoxic T cells and increasing the proliferation of NK cells and the production of the cytokine interferon-gamma.
According to Compass, CTX-471 binds to a unique site within CD137. In lab dishes, the drug induced interferon-gamma production by human T cells and showed a level of activation that fell between the super-strong activity of Bristol Myers Squibb’s urelumab and the weaker action of Pfizer’s utomilumab—two other CD137 antibodies that have entered clinical trials.
The researchers then tested the drug in mice with intact immune systems. In a colon carcinoma model, the drug showed potent anti-tumor effects and improved overall survival. At its optimal dose level, the drug achieved complete tumor regressions in all eight treated mice. The mice were also completely protected from tumor regrowth after being re-challenged with tumor cells, “indicating the establishment of long-term antitumor immunity,” the scientists reported.
Similar effects were also observed across multiple doses in mouse models of lymphoma and triple-negative breast cancer.
Compass scientists noted that CTX-471 was even active against large tumors. In comparison, the urelumab clone, as well as other immuno-oncology antibodies targeting PD-1/L1, CTLA-4 and OX40, failed to trigger complete tumor regressions or substantially reduce tumor growth.
Further analysis revealed that treatment with CTX-471 changed the tumor microenvironment. It increased the total number of tumor-infiltrating T cells, while the level of immune-suppressive Tregs within tumors dropped sharply. Among those T cells that entered the tumors, the researchers also observed decreased expression of the immune checkpoint markers TIGIT and PD-1.
Interestingly, even though CTX-471 showed lower immune stimulation activity than urelumab did in cell cultures, Compass' drug appeared to perform better in living animals. At the lowest tested dose level, CTX-471 drug prompted complete tumor clearance in seven of the eight mice and significantly prolonged the animals’ lives compared with control mice. In contrast, a urelumab-like antibody only led to tumor regression in 3 of 8 mice and didn’t offer much in the way of survival benefits.
The $132 million Compass raised in a series A funding round in 2018 reflects a wider interest in CD137 as a cancer target. Gilead Sciences is collaborating with Agenus on AGEN2373, which entered the clinic last fall. Amgen in 2018 paid $50 million upfront for rights to Molecular Partners’ MP0310, a 4-1BB-FAP bispecific molecule that’s also now in phase 1 testing. Incyte previously shelled out $120 million for a broad partnership with Netherlands biotech Merus that includes a collaboration to develop an anti-PD-L1/CD137 bispecific antibody coded MCLA-145. It's also being tested in a phase 1 trial.
One problem with urelumab—the first anti-CD137 antibody to enter the clinic—is that it could induce inflammatory liver toxicity at low doses, limiting its therapeutic window. In mouse studies conducted by Compass scientists, CTX-471 did cause a systemic immune response, but it was weak and it didn't result in liver inflammation, they reported.