WTX-518, a conditionally activated IL-18 INDUKINETM molecule that resists suppression by IL-18BP, led to complete tumor regressions in preclinical models

WTX-712, a conditionally activated IL-21 INDUKINETM molecule has potent antitumor activity in preclinical models with a differentiated immune activation mechanism

WATERTOWN, Mass., April  05, 2024  (GLOBE NEWSWIRE) -- Werewolf Therapeutics, Inc. (the "Company" or "Werewolf") (Nasdaq: HOWL), an innovative biopharmaceutical company pioneering the development of conditionally-activated therapeutics engineered to stimulate the body's immune system for the treatment of cancer, is presenting preclinical data on development candidates WTX-518 and WTX-712 in posters at the American Association for Cancer Research (AACR) Annual Meeting, taking place April 5-10 in San Diego, California.

"We are excited to share that both WTX-518 and WTX-712 demonstrate powerful immunotherapeutic effects in preclinical models," said Daniel J. Hicklin, Ph.D., President and Chief Executive Officer of Werewolf. "WTX-518 exhibits remarkable tumor-selective activation, resistance to IL-18BP and robust immune activation, overcoming key hurdles in the use of this promising cytokine in cancer therapy. WTX-712 acts through a unique mechanism that robustly activates tumor-specific T lymphocytes with an expanded therapeutic window through its selective release of wild-type IL-21 in the TME. These data collectively highlight the innovative strategies we are pursuing to further expand the repertoire of unique immune stimulating cytokine mechanisms in the fight against cancer."

Results highlighting WTX-518 findings are summarized in a poster titled, "Discovery of WTX-518, an IL-18 pro-drug that is conditionally activated within the tumor microenvironment and induces regressions in mouse tumor models" (Abstract #4074). Key takeaways reveal that WTX-518:

• is inducible, and its in vitro activity is not impeded by IL-18BP;

• selectively delivers active binding protein resistant (BPR) IL-18 to the tumor microenvironment (TME); and

• promotes increased influx and activation of NK cells and polyfunctional CD8 T cells in the TME, and demonstrates complete tumor regression in the MC38 mouse tumor model.

The WTX-712 data are summarized in a poster titled, "WTX-712, a conditionally active IL-21 INDUKINE molecule, induces a strong anti-tumor phenotype through a differentiated mechanism" (Abstract #4078). Key takeaways reveal that:

• WTX-712 demonstrates inducibility and antitumor activity with regressions in the MC38 mouse tumor model;

• IL-21 HLE (half-life extended) has superior anti-tumor efficacy compared to IL-2 HLE therapy in mouse tumor models that are highly resistant to anti-PD-1/PD-L1 treatment, in part due to the activation of type-I IFN pathways; and

• IL-21 HLE promotes sustained expansion and activation of tumor infiltrating CD8 T cells with increased polyfunctionality and induces expression of cytotoxic effector molecules (Granzyme A, Granzyme B, and perforin).

Both posters can be viewed in person from 9:00 a.m. to 12:30 p.m. PDT on Tuesday, April 9, during the session category "Immunology" at Poster Section 4, and will be available on our website

Werewolf plans to develop WTX-518 and WTX-712 as potential immunotherapies in refractory and/or immunologically unresponsive tumors.